CiteULike: Tag degeneration

Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice.

Zhenglin Yang — 2008-08-14T19:48:00-00:00

The Journal of clinical investigation, Vol. 118, No. 8. (1 August 2008), pp. 2908-2916.

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA.

Lars G Fritsche — 2008-06-24T19:23:27-00:00

Nature genetics (30 May 2008)

Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina. Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology. Signals at 10q26 center over two nearby genes, ARMS2 (age-related maculopathy susceptibility 2, also known as LOC387715) and HTRA1 (high-temperature requirement factor A1), suggesting two equally probable candidates. Here we show that a deletion-insertion polymorphism in ARMS2 (NM_001099667.1:c.(*)372_815del443ins54) is strongly associated with AMD, directly affecting the transcript by removing the polyadenylation signal and inserting a 54-bp element known to mediate rapid mRNA turnover. As a consequence, expression of ARMS2 in homozygous carriers of the indel variant is not detectable. Confirming previous findings, we demonstrate a mitochondrial association of the normal protein and further define its retinal localization to the ellipsoid region of the photoreceptors. Our data suggest that ARMS2 has a key role in AMD, possibly through mitochondria-related pathways.

A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.

Z Yang — 2008-05-27T17:34:54-00:00

Science (New York, N.Y.), Vol. 314, No. 5801. (10 November 2006), pp. 992-993.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

Clostridial strain degeneration

Eva Kashket — 2006-06-20T15:07:16-00:00

FEMS Microbiology Reviews, Vol. 17, No. 3. (1995), pp. 307-315.

Strain degeneration, the loss of the capacity to produce solvents and form spores, typically occurs when Clostridium acetobutylicum and related clostridia are repeatedly subcultured in batch culture or grown in continuous culture, as opposed to being grown from germinated, heat-treated spores. Several mechanisms for degeneration have been identified thus far. (i) Degeneration can be caused by excessive acidification of the culture during exponential growth. We present data interpreted to mean that C. beijerinckii (formerly C. acetobutylicum) NCIMB 8052 cells ferment glucose to acetic and butyric acids at an uncontrolled rate, so that, during rapid growth, the rate of acid production can exceed the rate of induction of the solventogenic pathway enzymes. As a result, the medium pH drops to bactericical levels, and the cells cannot switch to solventogenesis and sporulation. The clostridia seem to be poised either to produce excess acids, or to initiate solventogenesis, depending on small differences in the rates of growth. (ii) We have isolated transposon-insertion mutants of C. beijerinckii NCIMB 8052 that are resistant to degeneration, suggesting the involvement of a regulatory region of the clostridial chromosome. (iii) Involvement of a global regulatory gene has been inferred in C. beijerinckii NCIMB 8052 which degenerates irreversibly in chemostat culture. (iv) Impairment of butanol formation due to a defect in NADH generation has been reported in an oligosporogenous strain which can revert to the non-degenerate phenotype. (v) In continuous culture, degenerate cells may be selected because they continue to divide, while the non-degenerate cells stop dividing and start differentiating.

A follow-up study of neurologic and radiographic findings in working German Shepherd Dogs with and without degenerative lumbosacral stenosis.

F Steffen — 2007-11-28T12:51:27-00:00

J Am Vet Med Assoc, Vol. 231, No. 10. (15 November 2007), pp. 1529-1533.

Objective-To identify radiographic abnormalities associated with degenerative lumbosacral stenosis (DLSS) in German Shepherd Dogs (GSDs) and determine whether specific radiographic abnormalities could be used to identify dogs at risk of developing DLSS. DesignCohort study. Animals-33 GSDs working as police dogs. Procedures-Results of physical, neurologic, and orthopedic examinations were used to identify dogs with DLSS. Survey radiography of the lumbosacral junction was performed, and radiographs were compared with radiographs obtained 3 years earlier. Results-DLSS was diagnosed in 15 of the 33 (45%) dogs. Thirteen of the 15 dogs with DLSS and 14 of the 18 dogs without DLSS had radiographic abnormalities of the lumbosacral junction. Twenty-two (67%) dogs were able to perform unrestricted duties, including 3 dogs with suspected DLSS. Six (18%) dogs had been excluded from active duty during the period of surveillance because of DLSS. Significant progression in specific clinical and radiographic signs was detected, but multiple logistic regression analysis did not identify any radiographic signs that could be used to predict the development of DLSS. Conclusions and Clinical Relevance-Results suggested that survey radiography cannot be used to predict development of DLSS in working GSDs.

Cerebellar cortical degeneration with selective granule cell loss in Bavarian mountain dogs

T Flegel — 2007-07-30T04:59:18-00:00

Journal of Small Animal Practice, Vol. 48, No. 8. (2007), pp. 462-465.

Three Bavarian mountain dogs aged between 18 and 20 months, not related to each other, were presented with chronic signs of cerebellar dysfunction. On sagittal T2-weighted magnetic resonance imaging brain images, the tentative diagnosis of cerebellar hypoplasia was established based on an enlarged cerebrospinal fluid space around the cerebellum and an increased cerebrospinal fluid signal between the folia. Post-mortem examination was performed in one dog and did show an overall reduction of cerebellar size. On histopathologic examination, a selective loss of cerebellar granule cells with sparing of Purkinje cells was evident. Therefore, the Bavarian mountain dog is a breed where cerebellar cortical degeneration caused by the rather exceptional selective granule cell loss can be seen as cause of chronic, slowly progressive cerebellar dysfunction starting at an age of several months.

Nonlinear enhancement and segmentation algorithm for the detection of age-related macular degeneration (AMD) in human eye's retina

K Rapantzikos — 2005-11-22T14:52:20-00:00

Image Processing, 2001. Proceedings. 2001 International Conference on, Vol. 3 (2001), pp. 1055-1058 vol.3.

Assessment of the risk for the development of age related macular degeneration requires reliable detection of retinal abnormalities that are considered as precursors of the disease. A typical sign for the latter are the so-called drusen, which appear as abnormal white-yellow deposits on the retina. This paper presents a novel segmentation algorithm for automatic detection of abnormalities in images of the human eye's retina, acquired from a depth-vision camera. Conventional image processing techniques are sensitive to non-uniform illumination and nonhomogeneous background, which obstructs the derivation of reliable results for a large set of different images. Homomorphic filtering and a multilevel variant of histogram equalization are used for non-uniform illumination compensation and enhancement. We develop a novel segmentation technique, the histogram-teased adaptive local thresholding (HALT), to detect drusen in retina images by extracting the useful information without being affected by the presence of other structures. We provide experimental results from the application of our technique to real images, where certain abnormalities (drusen) have slightly different characteristics from the background and are hard to be segmented by other conventional techniques

Painful diabetic neuropathy: a cross-sectional survey of health state impairment and treatment patterns.

T Tölle — 2007-05-30T14:43:36-00:00

J Diabetes Complications, Vol. 20, No. 1. (b 2006), pp. 26-33.

AIMS: To determine the patient burden of painful diabetic peripheral neuropathy (DPN) with respect to pain intensity and impact on patient functioning and to characterize relevant DPN treatment patterns. METHODS: Patients (n=140) with painful DPN identified during an observational survey of neuropathic pain syndromes in six European countries were included in the current analysis. Patients primarily recruited from community-based general practices answered a questionnaire that included pain severity and interference items from the modified Short-Form Brief Pain Inventory, the EuroQol survey, and questions related to productivity and health resource utilization. Physicians provided information on disease duration and current medications prescribed for painful DPN and pain-related comorbidities. RESULTS: The mean patient age was 65.6+/-11.2 years; 58% of the patients were >or=65 years. Duration of painful DPN was >1 year in 74% of patients. The mean Pain Severity Index was 5.0+/-2.0; 57% of patients reported moderate pain and 25% reported severe pain. Patients reported moderate interference with functioning despite 91% of patients reporting use of prescription medications for painful DPN including antiepileptics (56%), standard analgesics (63%), and amitriptyline (26%). Use of prescription medication for concomitant anxiety, depression, or sleep disturbance was reported for 43% of the patients. Disruption in employment was reported by 35% of the patients. Pain severity was significantly associated with reduced health state valuation (P<.001), greater pain interference scores (P<.001), greater employment disruption (P<.05), and more physician visits (P<.05). CONCLUSIONS: Painful DPN is associated with substantial patient burden resulting from interference with daily functioning, especially in patients with suboptimal pain management.

Assessment of Epidermal Nerve Fibers: A New Diagnostic and Predictive Tool for Peripheral Neuropathies.

Gigi Ebenezer — 2008-01-09T17:34:28-00:00

J Neuropathol Exp Neurol, Vol. 66, No. 12. (December 2007), pp. 1059-1073.

Today, skin biopsies can play an important role in the diagnosis of peripheral nerve disorders and have yielded another diagnostic tool for the neurologist. One of the commonly reported neuropathologic abnormalities observed in skin biopsies is a reduction of epidermal nerve density. Analyzing the changes in the morphology and density of epidermal nerves is of immense diagnostic and prognostic value in peripheral neuropathies. These changes also provide an assessment of disease progression and of tissue responses to regenerative treatments. Combined with immunohistochemical studies, newly evolved skin biopsy and epidermal count techniques have the potential to provide significant information about the pathogenesis of many peripheral nervous system diseases. They have great potential for impacts on both research and clinical approaches to treatment. Evolution of a standardized and validated counting methodology and significant advances in procuring skin biopsies have opened up a wide spectrum of applications that make the technology easy to apply in practice. The application of this technology may lead to early detection of many common peripheral nerve diseases and an enhanced understanding of disease onset and progression. In this article we review the state of current research and clinical practice in the use of skin biopsies and epidermal nerve densities.

Cellular Zn(2+) chelators cause "dying-back" neurite degeneration associated with energy impairment.

Yi Yang — 2007-07-24T13:34:04-00:00

J Neurosci Res (12 July 2007)

Most cellular zinc is tightly associated with metalloproteins and other Zn(2+)-dependent proteins, which along with cellular Zn(2+) compartments may coordinately regulate cytoplasmic free Zn(2+) levels in the picomolar range. Moreover, Zn(2+)-containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn(2+) and/or Zn(2+) protein complexes in neurons. It is therefore interesting to examine whether cellular Zn(2+) levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenanthroline, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), and zinquin, selectively elicit axon and dendrite degeneration but leave the cell body intact in sympathetic neurons. The process begins distally and then moves retrogradely, with a distinct "dying-back" pattern. An inactive isomer of 1,10-phenanthroline failed to cause neuite degeneration, and these chelators mediated their effects by selectively chelating Zn(2+), but not other metals. Moreover, neurite degeneration was associated with a decrease in neuritic ATP levels and was caused by energy failure, because an exogenous supply of nicotinamide adenine dinucleotide (NAD) or its precursor nicotinamide suppressed the degeneration by delaying axonal ATP reduction caused by Zn(2+) depletion. Blockage of autophagy by 3-methyladenine provided partial protection against degeneration of terminal axons or dendrites; there was, however, no obvious alteration in that of medial portions. Collectively, our results show that cellular Zn(2+) depletion induces a "dying-back" degeneration characterized by an NAD- and autophagy-dependent process, independently of neurite elongation dynamics. (c) 2007 Wiley-Liss, Inc.

Retraction of synapses and dendritic spines induced by off-target effects of RNA interference.

VA Alvarez — 2006-07-29T01:29:30-00:00

J Neurosci, Vol. 26, No. 30. (26 July 2006), pp. 7820-7825.

RNA interference (RNAi), which allows selective gene silencing, has been proposed for functional genomic analysis and for the treatment of human disease. However, induction of RNAi in mammalian cells by expression of double-stranded RNA can activate innate antiviral response pathways that perturb off-target gene expression. The activation and functional consequences of these effects in neurons are unknown. We find that expression of subsets of short hairpin RNAs (shRNAs) in rat hippocampal pyramidal neurons can have off-target effects that reduce the complexity of dendritic arbors and trigger the loss of dendritic spines. Morphological changes are accompanied by electrophysiological perturbations in passive membrane properties and a decrease in the number and strength of excitatory and inhibitory synapses. These perturbations depend on the shRNA sequence and are independent of the identity of the targeted protein. Our results indicate that off-target effects of RNAi severely perturb neuronal structure and function and may lead to the functional withdrawal of affected cells from the brain circuitry.

The membrane attack complex of the complement system is essential for rapid Wallerian degeneration.

V Ramaglia — 2007-07-24T13:32:02-00:00

J Neurosci, Vol. 27, No. 29. (18 July 2007), pp. 7663-7672.

The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.

Contemporary management of neuropathic pain for the primary care physician.

H Chen — 2007-05-30T14:25:49-00:00

Mayo Clin Proc, Vol. 79, No. 12. (December 2004), pp. 1533-1545.

Neuropathic pain (NP), caused by a primary lesion or dysfunction in the nervous system, affects approximately 4 million people in the United States each year. It is associated with many diseases, including diabetic peripheral neuropathy, postherpetic neuralgia, human immunodeficiency virus-related disorders, and chronic radiculopathy. Major pathophysiological mechanisms include peripheral sensitization, sympathetic activation, disinhibition, and central sensitization. Unlike most acute pain conditions, NP is extremely difficult to treat successfully with conventional analgesics. This article introduces a contemporary management approach, that is, one that incorporates nonpharmacological, pharmacological, and interventional strategies. Some nonpharmacological management strategies include patient education, physical rehabilitation, psychological techniques, and complementary medicine. Pharmacological strategies include the use of first-line agents that have been supported by randomized controlled trials. Finally, referral to a pain specialist may be indicated for additional assessment, interventional techniques, and rehabilitation. Integrating a comprehensive approach to NP gives the primary care physician and patient the greatest chance for success.

Soluble complement receptor 1 protects the peripheral nerve from early axon loss after injury.

V Ramaglia — 2008-04-02T11:43:24-00:00

The American journal of pathology, Vol. 172, No. 4. (April 2008), pp. 1043-1052.

Complement activation is a crucial early event in Wallerian degeneration. In this study we show that treatment of rats with soluble complement receptor 1 (sCR1), an inhibitor of all complement pathways, blocked both systemic and local complement activation after crush injury of the sciatic nerve. Deposition of membrane attack complex (MAC) in the nerve was inhibited, the nerve was protected from axonal and myelin breakdown at 3 days after injury, and macrophage infiltration and activation was strongly reduced. We show that both classical and alternative complement pathways are activated after acute nerve trauma. Inhibition of the classical pathway by C1 inhibitor (Cetor) diminished, but did not completely block, MAC deposition in the injured nerve, blocked myelin breakdown, inhibited macrophage infiltration, and prevented macrophage activation at 3 days after injury. However, in contrast to sCR1 treatment, early signs of axonal degradation were visible in the nerve, linking MAC deposition to axonal damage. We conclude that sCR1 protects the nerve from early axon loss after injury and propose complement inhibition as a potential therapy for the treatment of diseases in which axon loss is the main cause of disabilities.

Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration.

M Komatsu — 2007-10-12T11:17:07-00:00

Proc Natl Acad Sci U S A, Vol. 104, No. 36. (4 September 2007), pp. 14489-14494.

Autophagy is a regulated lysosomal degradation process that involves autophagosome formation and transport. Although recent evidence indicates that basal levels of autophagy protect against neurodegeneration, the exact mechanism whereby this occurs is not known. By using conditional knockout mutant mice, we report that neuronal autophagy is particularly important for the maintenance of local homeostasis of axon terminals and protection against axonal degeneration. We show that specific ablation of an essential autophagy gene, Atg7, in Purkinje cells initially causes cell-autonomous, progressive dystrophy (manifested by axonal swellings) and degeneration of the axon terminals. Consistent with suppression of autophagy, no autophagosomes are observed in these dystrophic swellings, which is in contrast to accumulation of autophagosomes in the axonal dystrophic swellings under pathological conditions. Axonal dystrophy of mutant Purkinje cells proceeds with little sign of dendritic or spine atrophy, indicating that axon terminals are much more vulnerable to autophagy impairment than dendrites. This early pathological event in the axons is followed by cell-autonomous Purkinje cell death and mouse behavioral deficits. Furthermore, ultrastructural analyses of mutant Purkinje cells reveal an accumulation of aberrant membrane structures in the axonal dystrophic swellings. Finally, we observe double-membrane vacuole-like structures in wild-type Purkinje cell axons, whereas these structures are abolished in mutant Purkinje cell axons. Thus, we conclude that the autophagy protein Atg7 is required for membrane trafficking and turnover in the axons. Our study implicates impairment of axonal autophagy as a possible mechanism for axonopathy associated with neurodegeneration.

Primary afferent dendrite degeneration as a cause of tinnitus.

CA Bauer — 2007-05-30T14:16:07-00:00

J Neurosci Res, Vol. 85, No. 7. (15 May 2007), pp. 1489-1498.

Chronic tinnitus affects millions of people, but the mechanisms responsible for the development of this abnormal sensory state remain poorly understood. This study examined the type and extent of cochlear damage that occurs after acoustic trauma sufficient to induce chronic tinnitus in rats. Tinnitus was evaluated by using a conditioned suppression method of behavioral testing. Cochlear damage was assessed 6 months after acoustic trauma. There was minimal loss of inner and outer hair cells in the exposed cochleas of subjects demonstrating evidence of tinnitus. However, a significant loss of large-diameter fibers in the osseous spiral lamina of exposed cochleas of trauma subjects was observed. The significance of this finding in the context of a model of tinnitus is discussed. (c) 2007 Wiley-Liss, Inc.

Axonal degeneration in motor neuron disease.

LR Fischer — 2007-10-24T15:16:46-00:00

Neurodegener Dis, Vol. 4, No. 6. (2007), pp. 431-442.

Growing evidence from animal models and patients with amyotrophic lateral sclerosis (ALS) suggests that distal axonal degeneration begins very early in this disease, long before symptom onset and motor neuron death. The cause of axonal degeneration is unknown, and may involve local axonal damage, withdrawal of trophic support from a diseased cell body, or both. It is increasingly clear that axons are not passive extensions of their parent cell bodies, and may die by mechanisms independent of cell death. This is supported by studies in which protection of motor neurons in models of ALS did not significantly improve symptoms or prolong lifespan, likely due to a failure to protect axons. Here, we will review the evidence for early axonal degeneration in ALS, and discuss possible mechanisms by which it might occur, with a focus on oxidative stress. We contend that axonal degeneration may be a primary feature in the pathogenesis of motor neuron disease, and that preventing axonal degeneration represents an important therapeutic target that deserves increased attention. Copyright (c) 2007 S. Karger AG, Basel.

Aging Delays the Regeneration Process following Sciatic Nerve Injury in Rats.

YJ Wang — 2007-06-04T10:10:16-00:00

J Neurotrauma, Vol. 24, No. 5. (May 2007), pp. 885-894.

The present study investigated the effect of aging on muscle reinnervation in rats following a crush nerve injury. Using confocal laser scanning microscopy, we examined the spatial correlation of terminal Schwann cells (TSCs) or axon terminals with acetylcholine receptor (AChR) sites at neuromuscular junctions (NMJs). Compared to young rats (4 months of age), aged rats (24 months of age) demonstrated damaged TSC extensions and delayed regeneration. Post-injury endplate abnormalities in aged rats correlated with the degree of TSC degeneration. In the late stages of reinnervation, pathologic changes were seen in old rats, including multiple innervations, terminal sprouting, and poorly formed collateral innervation in NMJs. Our results suggest that the impaired TSC-axon interaction in aged rats delays the reinnervation process.

Delayed combinatorial treatment with flavopiridol and minocycline provides longer term protection for neuronal soma but not dendrites following global ischemia

Iyirhiaro — 2008-04-21T18:34:53-00:00

Journal of Neurochemistry, Vol. 105, No. 3. (May 2008), pp. 703-713.

Abeta, tau and ApoE4 in Alzheimer's disease: the axonal connection.

R Adalbert — 2007-08-01T13:26:48-00:00

Trends Mol Med, Vol. 13, No. 4. (April 2007), pp. 135-142.

Mutations in amyloid precursor protein (APP), tau and apolipoprotein E4 (ApoE4) lead to Alzheimer's disease (AD) or related pathologies. Pathogenesis and interactions between these pathways have been studied in mouse models. Here, we highlight the fact that axons are important sites of cellular pathology in each pathway and propose that pathway convergence at the molecular level might occur in axons. Recent developments suggest that axonal transport of APP influences beta-amyloid deposition and that tau regulates axonal transport. ApoE4 influences both axonal tau phosphorylation and amyloid-induced neurite pathology. Thus, a better understanding of axonal events in AD might help connect the pathogenic mechanisms of beta-amyloid, ApoE4 and tau, indicating the most important steps for therapeutic targeting.

FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury.

S Casha — 2007-08-15T14:35:19-00:00

Exp Neurol, Vol. 196, No. 2. (December 2005), pp. 390-400.

After spinal cord injury (SCI), apoptosis of neurons and oligodendrocytes is associated with axonal degeneration and loss of neurological function. Recent data have suggested a potential role for FAS death receptor-mediated apoptosis in the pathophysiology of SCI. In this study, we examined the effect of FAS deficiency on SCI in vitro and in vivo. FAS(Lpr/lpr) mutant mice and wildtype background-matched mice were subjected to a T5-6 clip compression SCI, and complementary studies were done in an organotypic slice culture model of SCI. Post-traumatic apoptosis in the spinal cord, which was seen in neurons and oligodendrocytes, was decreased in the FAS-deficient mice both in vivo and in vitro particularly in oligodendrocytes. FAS deficiency was also associated with improved locomotor recovery, axonal sparing and preservation of oligodendrocytes and myelin. However, FAS deficiency did not result in a significant increase in surviving neurons in the spinal cord at 6 weeks after injury, likely reflecting the importance of other cell death mechanisms for neurons. We conclude that inhibition of the FAS pathway may be a clinically attractive neuroprotective strategy directed towards oligodendroglial and axonal preservation in the treatment of SCI and neurotrauma.

BDNF preserves the dendritic morphology of alpha and beta ganglion cells in the cat retina after optic nerve injury.

AJ Weber — 2008-08-20T10:12:40-00:00

Investigative ophthalmology & visual science, Vol. 49, No. 6. (June 2008), pp. 2456-2463.

PURPOSE: To examine whether brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the mammalian retina, also plays a role in preserving the dendritic integrity of the surviving ganglion cells after optic nerve injury. METHODS: Single ganglion cells from cats that underwent unilateral optic nerve crush and received no treatment or nerve crush combined with intravitreous treatment of the affected eye with BDNF were labeled intracellularly, reconstructed using confocal microscopy, and compared quantitatively. RESULTS: Optic nerve injury produced a significant decrease in the soma, dendritic field size, and dendritic complexity of alpha cells. beta Cells also displayed a significant decrease in soma size, but their dendritic fields were not affected as severely as those of alpha cells. Intravitreous treatment of the eye with BDNF at the time of injury preserved the normal somal and dendritic morphologies of both alpha and beta cells. CONCLUSIONS: BDNF, in addition to promoting ganglion cell survival, plays an important role in preserving the somal and dendritic morphologies of the surviving ganglion cells, a necessary precursor to maintaining normal visual function. Ganglion cells, however, are not created equal with respect to their responses to nerve injury or to treatment of the eye with BDNF. Thus, development of effective treatment strategies for preserving ganglion cell function in optic nerve-related diseases mandates a clearer understanding of the cellular response characteristics of the specific neurons involved.

Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease.

AJ Szalai — 2008-04-09T11:16:28-00:00

Molecular immunology, Vol. 44, No. 12. (May 2007), pp. 3132-3136.

Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study, we used C3(-/-) mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3(+/-) mice (with serum C3 levels 50% that of wild-type mice) developed EAE with a severity intermediate between wild-type and C3(-/-) mice. Importantly transfer of wild-type encephalitogenic T cells to C3(-/-) mice resulted in attenuated EAE. C3(-/-) mice with EAE had fewer CD4(+) and CD8(+) T cells in the CNS and 50% fewer of these cells produced IFN-gamma compared to wild-type mice. When treated with anti-CD3 antibody, CD4(+) T cells from wild-type and C3(-/-) mice had similar activation profiles as judged by IFN-gamma production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3(-/-) mice. T cells from primed C3(-/-) mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.

Nitric oxide in damage, disease and repair of the peripheral nervous system.

DW Zochodne — 2008-07-24T14:21:56-00:00

Cellular and molecular biology (Noisy-le-Grand, France), Vol. 51, No. 3. (5 September 2005), pp. 255-267.

Peripheral nerves provide essential connections between the central nervous system and muscles, autonomic structures and sensory organs. Nitric oxide (NO) participates in critical actions involving several aspects of peripheral nerve function and disease. It offers important roles in "normal" afferent signaling of pain through the dorsal horn of the spinal cord and in autonomic control through nitrergic innervation. NO is generated during the fundamental processes of Wallerian degeneration of peripheral nerves following injury that bear on subsequent regenerative events. Through its actions on vasa nervorum, the blood supply to nerves, NO participates in microvascular changes following injury but also has direct roles in axon and myelin breakdown and "clearance" prior to regeneration. During such processes, NO contributes to the development of neuropathic pain. Excessive local levels of NO during inflammation may damage axons and growth cones. Low-grade chronic rises in NO may also contribute toward peripheral nerve damage, or neuropathy in diabetes. In this review, we consider the evidence for these roles and their potential importance in disease and repair of peripheral nerves.

Ethanol-related increases in degenerating bodies in the Purkinje neuron dendrites of aging rats.

CA Dlugos — 2008-08-20T10:01:26-00:00

Brain research, Vol. 1221 (24 July 2008), pp. 98-107.

Chronic ethanol consumption in aging rats results in regression of Purkinje neuron (PN) dendritic arbors ([Pentney, 1995 Measurements of dendritic pathlengths provide evidence that ethanol-induced lengthening of terminal dendritic segments may result from dendritic regression. Alcohol Alcohol. 30, 87-96]), loss of synapses (Dlugos and Pentney, 1997), dilation of the smooth endoplasmic reticulum (SER), and the formation of degenerating bodies within PN dendrites ([Dlugos, C.A., 2006a. Ethanol-Related Smooth Endoplasmic Reticulum Dilation in Purkinje Dendrites of Aging Rats. Alcohol., Clin. Exp. Res. 30, 883-891,Dlugos, C.A., 2006b. Smooth endoplasmic reticulum dilation and degeneration in Purkinje neuron dendrites of aging ethanol-fed female rats. Cerebellum. 5, 155-162]). Dilation of the SER and the formation of degenerating bodies may be a predictor of dendritic regression. Ethanol-induced effects on mitochondria may be involved as mitochondria cooperate with the SER to maintain calcium homeostasis. The purpose of this study was to determine whether degenerating body number and mitochondrial density and structure are altered by chronic ethanol treatment in PN dendrites. Male, Fischer 344 rats, 12 months of age, were fed an ethanol or pair-fed liquid diet, or rat chow for a period of 10, 20, or 40 weeks (15 rats/treatment; 45 rats/treatment duration). Ethanol-fed rats received 35% of their calories as ethanol. At the end of treatment, all animals were euthanized, perfused, and tissue prepared for electron microscopy. The densities of degenerating bodies and mitochondria, mitochondrial areas, and the distance between the SER and the mitochondria were measured. Results showed that there was an ethanol-related increase in degenerating bodies compared to controls at 40 weeks. Ethanol-induced alterations to mitochondria were absent. Correlation of the present results with those of previous studies suggest that degenerating bodies may be formed from membrane reabsorption during dendritic regression or from degenerating SER whose function has been compromised by dilation.

Fine structural changes of muscle spindles in the gracile axonal dystrophy mutant mouse.

A Takagi — 2008-08-07T12:08:08-00:00

Virchows Archiv : an international journal of pathology, Vol. 428, No. 4-5. (July 1996), pp. 289-296.

Fine structural changes of muscle spindles in the extensor digitorum longus of the gracile axonal dystrophy mutant mouse were studied from 20 to 120 postnatal days. Degenerative nerve endings in muscle spindles were first recognized at 20 postnatal days. The sensory nerve endings were usually swollen with decrease of cell organelles, and the cytoplasm was electron-lucent. At 50 postnatal days, atrophic nerve endings were frequently observed in the narrow spaces between the indented cell membrane of intrafusal muscle cells and the basement membrane. In addition to degenerative and atrophic changes, regenerative axons showing fine sprouts (with or without Schwann cell projections) appeared in the sensory nerve endings at this time. At 80 postnatal days, sensory nerve endings frequently showed dystrophic changes characterized by axonal dilatation with accumulations of neurofilaments, tubulovesicular structures, mitochondria and myelin-like figures. These findings suggest that axonal transport in the sensory nerve endings is impaired in this mutant mouse. Motor nerve endings were usually well preserved and normal structures even at 80 postnatal days. Intrafusal fibrosis, decrease in number of sensory nerve endings and atrophy of intrafusal muscle fibres were clearly recognized by 100 days of age.

Acute energy restriction triggers Wallerian degeneration in mouse.

S Alvarez — 2008-07-24T14:21:31-00:00

Experimental neurology, Vol. 212, No. 1. (July 2008), pp. 166-178.

Acute exposure of peripheral axons to the free radical Nitric Oxide (NO) may trigger conduction block and, if prolonged, Wallerian degeneration. It was hypothesized that this neurotoxic effect of NO may be due primarily to energy restriction by inhibition of mitochondrial respiration. We compared the neurotoxic effect of NO with the effect of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) on electrically active axons of mouse sciatic nerve. The right tibial nerve was stimulated at the ankle. Muscle responses were recorded from plantar muscles and ascending nerve action potentials were recorded form the exposed sciatic nerve by means of a hook electrode. The sciatic nerve was focally immersed over a length of 1 cm in either phosphate buffered saline (PBS), a solution of approximately 4 microM NO obtained from 10 mM of the NO-donor DETA NONOate, or a solution of up to 1 mM DNP. Following 3 hours of 200 Hz stimulation, the nerves were washed in PBS for 1 hour, the surgical wounds were closed and the mice were left to recover. Following repetitive stimulation in PBS, the nerve responses recovered within 1 hour and the muscle responses within 1 day. The effects of focal acute exposure to NO or DNP were similar: (i) a transient conduction failure that rapidly normalized within one hour of washout and (ii) subsequent Wallerian degeneration of some axons confirmed at morphological studies. Taken together, these data support the hypothesis that neurotoxicity may be caused by energy restriction. Since the pharmacologic effect of NO and DNP was only transient, our data suggest that even a brief period of focal energy restriction can trigger Wallerian degeneration.

Dendritic and synaptic protection: is it enough to save the retinal ganglion cell body and axon?

JB Morquette — 2008-08-20T09:59:05-00:00

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society, Vol. 28, No. 2. (June 2008), pp. 144-154.

Glaucoma and other optic neuropathies have been traditionally viewed as diseases of the optic nerve that lead to retinal ganglion cell (RGC) degeneration. Accordingly, the primary aim of neuroprotective strategies has been to preserve RGC axons and soma. RGCs are complex and highly polarized central neurons, and their pathologic response in disease is likely to be an integration of signals from all cellular compartments-axons, soma, dendrites, and synaptic contacts. We focus on the role of dendrites and dendritic spines in normal neuronal function, neurologic disorders, and glaucoma. The need to understand the mechanisms underlying RGC dendrite and synapse degeneration in glaucoma and other optic neuropathies is compelling, as it may provide insight into novel therapeutic strategies to prevent vision loss.

Hereditary absence of complement C5 in adult mice influences Wallerian degeneration, but not retrograde responses, following injury to peripheral nerve.

L Liu — 2008-04-09T11:13:28-00:00

Journal of the peripheral nervous system : JPNS, Vol. 4, No. 2. (1999), pp. 123-133.

We have examined the role of complement component 5 (C5) in peripheral nerve fiber degeneration and regeneration, as well as in glial and neuronal cell responses in the central nervous system (CNS). Adult congenic mice lacking C5 (C5(-)) and the corresponding normal strain (C5(+)) were used. Macrophage recruitment as well as axonal and myelin sheath elimination were delayed from 1 to 21 days postinjury in C5(-) mice compared to the C5(+) group after sciatic nerve crush. Despite this, recovery of motor function was not delayed. In the CNS, microglial cells and astrocytes responded in the same way from 3 to 21 days after sciatic nerve injury in C5(-) and C5(+) mice, and the extent of neuron death following hypoglossal nerve avulsion was the same in both groups. These findings suggest that C5 and/or its derivatives play an important role in initiating the recruitment of macrophages to the injured nerve and, probably indirectly, in early remyelination of regenerating axons, but does not influence the longterm functional restoration or axotomy-induced nerve cell death. C5-derived molecules do not appear to participate in central glial cell responses to peripheral nerve injury. These findings elucidate new aspects on the functional role of the complement system in the peripheral nervous system following peripheral nerve injury.

Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration.

AT Dailey — 2008-04-09T11:12:54-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 18, No. 17. (1 September 1998), pp. 6713-6722.

After peripheral nerve injury, macrophages infiltrate the degenerating nerve and participate in the removal of myelin and axonal debris, in Schwann cell proliferation, and in axonal regeneration. In vitro studies have demonstrated the role serum complement plays in both macrophage invasion and activation during Wallerian degeneration of peripheral nerve. To determine its role in vivo, we depleted serum complement for 1 week in adult Lewis rats, using intravenously administered cobra venom factor. At 1 d after complement depletion the right sciatic nerve was crushed, and the animals were sacrificed 4 and 7 d later. Macrophage identification with ED-1 and CD11a monoclonal antibodies revealed a significant reduction in their recruitment into distal degenerating nerve in complement-depleted animals. Complement depletion also decreased macrophage activation, as indicated by their failure to become large and multivacuolated and their reduced capacity to clear myelin, which was evident at both light and electron microscopic levels. Axonal regeneration was delayed in complement-depleted animals. These findings support a role for serum complement in both the recruitment and activation of macrophages during peripheral nerve degeneration as well as a role for macrophages in promoting axonal regeneration.

Non-apoptotic neurite degeneration in apoptotic neuronal death: pivotal role of mitochondrial function in neurites.

K Ikegami — 2007-06-18T13:44:42-00:00

Neuroscience, Vol. 122, No. 3. (2003), pp. 617-626.

The length and thinness of neurites render them greatly susceptible to a variety of insults. Accumulating evidence suggests that neurite degeneration is not a passive, but an active and causative, event in some neurodegenerative diseases. Nonetheless, the mechanisms underlying neurite degeneration remain largely unknown. To elucidate the relevant mechanisms, we employed a mutant C57BL/Wld mouse with a unique phenotype of resistance to Wallerian degeneration, and separately analyzed the destruction of cell soma and neurites following treatment with vinblastine, a microtubule-disrupting agent, in superior cervical ganglion neurons. Vinblastine induced macromolecular synthesis-dependent cell death, which was indistinguishable between the wild-type and mutant mice. Evidence for a loss of mitochondrial cytochrome c, caspase activation, and nuclear fragmentation, has indicated that this type of cell death is entirely apoptotic. Consistent with this, the ATP level in the cell soma was well maintained and indistinguishable between wild-type and mutant mice. In neurites of wild-type neurons, vinblastine induced an early loss of mitochondrial membrane potential (MMP) and ATP depletion preceding caspase-independent degeneration, suggesting that this type of neurite degeneration is principally non-apoptotic. In contrast, neurites of mutant neurons were markedly resistant to vinblastine-induced degeneration, and both the MMP and the ATP content in the neurites were well maintained. Exposure of mutant neurons to carbonyl cyanide m-chlorophenyl-hydrazone, an uncoupler, caused extreme neurite degeneration following rapid MMP loss. Collectively, our findings suggest that: 1) neurite degeneration is regulated through a non-apoptotic process achieved by mitochondrial dysfunction in neurites; 2) the mitochondrial functional status is controlled separately in neurites and in the neuronal soma.

Neuronal death: where does the end begin?

Laura Conforti — 2007-03-09T09:11:59-00:00

Trends in Neurosciences, Vol. In Press, Corrected Proof

Neurodegenerative disorders involve death of cell bodies, axons, dendrites and synapses, but it is surprisingly difficult to determine the spatiotemporal sequence of events and the causal relationships among these events. Neuronal compartments often crucially depend upon one another for survival, and molecular defects in one compartment can trigger cellular degeneration in distant parts of the neuron. Here, we consider the novel approaches used to understand these biologically complex and technically challenging questions in amyotrophic lateral sclerosis, spinal muscular atrophy, glaucoma, Alzheimer's disease, Parkinson's disease and polyglutamine disorders. We conclude that there is partial understanding of what degenerates first and why, but that controversy remains the rule not the exception. Finally, we highlight strategies for resolving these fundamental issues.

Functional and morphological effects of repeated sodium arsenite exposure on rat peripheral sensory nerves.

Erika García-Chávez — 2007-05-30T13:32:00-00:00

J Neurol Sci (20 April 2007)

Exposure to inorganic arsenic (iAs) is known to result in peripheral neuropathy. To better understand the functional and morphological consequences of iAs exposure, we examined the electrophysiological and histological characteristics of the sensory sural nerves in adult Male Wistar rats following 30 days of sodium arsenite administration by gavage (10 mg/kg body weight/day). Arsenic (As) levels in the peripheral nerves of exposed animals were about 150 times greater than those in controls. Lipid peroxidation was also increased in iAs-exposed animals. Compound action potentials (CAPs) evoked in iAs-exposed nerves were characterized by a slower conduction velocity ( approximately 26%). iAs-exposed nerves also showed a trend towards a decreased CAP area ( approximately 35%). These electrophysiological changes were consistent with histological alterations such as a approximately 56% decrease in myelin thickness. In addition, the perimeter and transverse area of axons were reduced to 29% and 45% of control, respectively. Our results suggest that accumulation of As produced by iAs exposure induces oxidative damage, severe demyelination, and other morphological alterations in axons of peripheral nerves. These changes may, in turn, induce changes in the generation and propagation of action potentials in peripheral nerves, leading to decreased transmission of information from peripheral sensory organs to the central nervous system.

A gamma-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains.

P Spilman — 2008-08-02T00:48:51-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 30. (29 July 2008), pp. 10595-10600.

In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrP(Sc)) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the gamma-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this gamma-secretase inhibitor (GSI) might prevent dendritic degeneration in mice with scrapie. At 50 d postinoculation with Rocky Mountain Laboratory (RML) prions, mice were given GSI orally for 43-60 d. Because we did not expect GSI to produce a reduction of PrP(Sc) levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrP(Sc) formation in cultured cells. The combination of GSI and Qa reduced PrP(Sc) by approximately 95% in the neocortex and hippocampus but only approximately 50% in the thalamus at the site of prion inoculation. The GSI plus Qa combination prevented dendritic atrophy and loss, but GSI alone did not. Even though GSI reduced NICD levels to a greater extent than GSI plus Qa, it was unable to prevent dendritic degeneration. Whether a balance between NICD and dendrite growth-stimulating factors was achieved with GSI plus Qa but not GSI alone remains to be determined. Although the combination of GSI and Qa diminished PrP(Sc) in the brains of RML-infected mice, GSI toxicity prevented us from being able to assess the effect the GSI plus Qa combination on incubation times. Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined.

Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels.

EB George — 2008-04-09T14:19:18-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 15, No. 10. (October 1995), pp. 6445-6452.

We examined the role of extracellular calcium entry, the possible involvement of axonal calcium channels, and the potential protective effect of calcium channel and calpain antagonists in axotomy-induced axonal degeneration using murine dorsal root ganglia in cell culture. We found that calcium entry is both necessary and sufficient to induce axonal degeneration after axotomy, and may be inhibited by cobalt, manganese, dihydropyridines, and bepridil. Tetrodotoxin and omega-conotoxin are ineffective in preventing axonal degeneration. The activation of calpains also appears to be necessary and sufficient for axonal degeneration to proceed, and can be blocked with membrane-permeant leupeptin analogs and the oxirane aloxistatin. Although other calcium-activated events may occur, it appears that inhibition of calpain is sufficient to preserve the axon at the light microscope level, and to prevent axonal cytoskeleton degradation as detected by immunofluorescent staining. Our results suggest that axonal degeneration after axotomy involves the following sequence of events: (1) a lag-period after axotomy prior to the onset of axonal degeneration, (2) entry of calcium into the axon through an intact axolemma via a calcium-specific ion transport mechanism, (3) activation of calcium-dependent effector molecules such as calpains, (4) degradation of the axonal cytoskeleton. The details of the second step require further elucidation, and are of particular interest because this step is a potential target for therapies directed towards peripheral neuropathies.

Dying back type axonal degeneration of sensory nerve terminals in muscle spindles of the gracile axonal dystrophy (GAD) mutant mouse.

K Oda — 2007-05-30T16:11:16-00:00

Neuropathol Appl Neurobiol, Vol. 18, No. 3. (June 1992), pp. 265-281.

A disorder of the gracile axonal dystrophy (GAD) mutant mouse is characterized by a neuromuscular disease with sensory ataxia (detectable 30 days after birth) and paresis of the hindlimbs (detectable at 80 days). In the sensory ataxia stage, histological study of the primary sensory system shows that, in addition to the lesions in the central nervous system, peripherally projecting axons have also started to degenerate at their distal ends in muscle spindles. Although the structure of Ia fibre endings appear normal until 15 days after birth, initial changes in the annulo-spiral structure are detected around the 20th day by a degeneration of the terminal axons. Degeneration then progressed proximally and the secondary endings also start to degenerate. Neuron cell bodies located in the dorsal root ganglia are morphologically intact until the later stages. Chronological studies indicate that, although axonal degeneration progresses throughout life, it is accentuated during the rapid somatic growth period. Around 50 days of age, transient regeneration takes place at axonal endings when somatic growth has attained a plateau. Such primary sensory endings tend to be restored by fine, multiple axons which gain access to the intrafusal fibres through the original endoneurial tubes. Ultrastructural observations at the fully affected stage show intrafusal muscle fibres lying scattered within spindles due to loss of the fine network of inner capsule layers and an almost complete loss of sensory endings from the surface of intrafusal muscle fibres. These results indicate that this mutant mouse is a useful model for naturally occurring 'dying back' type axonal degeneration or 'central and peripheral distal axonopathies', and would provide significant information about the complete evolution of the pathological processes involved.

Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF

San Pun — 2006-02-24T04:26:03-00:00

Nature Neuroscience, Vol. 9, No. 3. (12 February 2006), pp. 408-419.

Comparison of cytokine expression profile during Wallerian degeneration of myelinated and unmyelinated peripheral axons.

Therapoj Cheepudomwit — 2007-12-13T10:34:26-00:00

Neurosci Lett (6 November 2007)

Changes in cytokine and chemokine expression during Wallerian degeneration have been studied using nerve transection models, which result in denervation of both myelinating and non-myelinating Schwann cells. Cytokine and chemokine response of non-myelinating Remak Schwann cells to loss of their axons is unknown. In this study, we compared the expression profile of various cytokines and chemokines in distal nerves after capsaicin-induced degeneration of unmyelinated axons to Wallerian degeneration induced by nerve transection. Upregulation of MCP-1, IL-2, IL-6 and IL-10 were seen in both groups but IL-1ss and LIF were primarily upregulated in Wallerian degeneration of the whole nerve and not in capsaicin-induced degeneration of unmyelinated axons. The activated macrophage response, as measured by an increase in ED-1 immunostaining, was more prominent in the transected sciatic nerves compared to capsaicin-treated nerves. These findings indicate that there are differences in the cytokine and chemokine response of myelinating and non-myelinating Schwann cells to loss of their axons, and add to a growing body of literature that points to greater heterogeneity among Schwann cells.

Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency.

A Aslam — 2007-05-30T14:50:37-00:00

Clin Immunol, Vol. 112, No. 1. (July 2004), pp. 24-29.

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.

Mechanisms of axon degeneration: From development to disease.

S Saxena — 2007-10-03T11:43:52-00:00

Prog Neurobiol, Vol. 83, No. 3. (October 2007), pp. 174-191.

Axon degeneration is an active, tightly controlled and versatile process of axon segment self-destruction. Although not involving cell death, it resembles apoptosis in its logics. It involves three distinct steps: induction of competence in specific neurons, triggering of degeneration at defined axon segments of competent neurons, and rapid fragmentation and removal of the segments. The mechanisms that initiate degeneration are specific to individual settings, but the final pathway of pruning is shared; it involves microtubule disassembly, axon swellings, axon fragmentation, and removal of the remnants by locally recruited phagocytes. The tight regulatory properties of axon degeneration distinguish it from passive loss phenomena, and confer significance to processes that involve it. Axon degeneration has prominent roles in development, upon lesions and in disease. In development, it couples the progressive specification of neurons and circuits to the removal of defined axon branches. Competence might involve transcriptional switches, and local triggering can involve axon guidance molecules and synaptic activity patterns. Lesion-induced Wallerian degeneration is inhibited in the presence of Wld(S) fusion protein in neurons; it involves early local, and later, distal degeneration. It has recently become clear that like in other settings, axon degeneration in disease is a rapid and specific process, which should not be confused with a variety of disease-related pathologies. Elucidating the specific mechanisms that initiate axon degeneration should open up new avenues to investigate principles of circuit assembly and plasticity, to uncover mechanisms of disease progression, and to identify ways of protecting synapses and axons in disease.

Axon & dendrite degeneration: Its mechanisms and protective experimental paradigms.

Tatsuro Koike — 2007-11-27T14:32:54-00:00

Neurochem Int (16 September 2007)

Accumulating evidence suggests that axon and dendrite (or neurite) degeneration both in vivo and in vitro requires self-destructive programs independent of cell death programs to segregate neurite degeneration from cell soma demise. This review will deal with the mechanisms of neurite degeneration caused by several experimental paradigms including trophic factor deprivation and Wallerian degeneration as well as those under pathological conditions. The involvement of autophagy and mitochondrial dysfunction is emphasized in these mechanisms. The mechanisms through which protective agents including the Wld(s) protein rescue neurites from degeneration or fail to do so will be discussed.

Why Is Wallerian Degeneration in the CNS So Slow?

Ben A Barres — 2007-06-18T12:25:36-00:00

Annu Rev Neurosci (12 June 2006)

Wallerian Degeneration (WD) is the set of molecular and cellular events by which degenerating axons and myelin are cleared after injury. Why WD is rapid and robust in the PNS but slow and incomplete in the CNS is a longstanding mystery. Here we review current work on the mechanisms of WD with an emphasis on deciphering this mystery and on understanding whether slow WD in the CNS could account for the failure of CNS axons to regenerate. Expected online publication date for the Annual Review of Neuroscience Volume 30 is June 16, 2007. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Contribution of degeneration of motor and sensory fibers to pain behavior and the changes in neurotrophic factors in rat dorsal root ganglion.

K Obata — 2007-08-01T13:52:31-00:00

Exp Neurol, Vol. 188, No. 1. (July 2004), pp. 149-160.

To elucidate the role of the degeneration of motor and sensory fibers in neuropathic pain, we examined the pain-related behaviors and the changes of brain-derived neurotrophic factor (BDNF) in the L4/5 dorsal root ganglion (DRG) and the spinal cord after L5 ventral rhizotomy. L5 ventral rhizotomy, producing a selective lesion of motor fibers, produced thermal hyperalgesia and increased BDNF expression in tyrosine kinase A-containing small- and medium-sized neurons in the L5 DRG and their central terminations within the spinal cord, but not in the L4 DRG. Furthermore, L5 ventral rhizotomy up-regulated nerve growth factor (NGF) protein in small to medium diameter neurons in the L5 DRG and also in ED-1-positive cells in the L5 spinal nerve, suggesting that NGF synthesized in the degenerative fibers is transported to the L5 DRG and increases BDNF synthesis. On the other hand, L5 ganglionectomy, producing a selective lesion of sensory fibers, produced heat hypersensitivity and an increase in BDNF and NGF in the L4 DRG. These data indicate that degeneration of L5 sensory fibers distal to the DRG, but not motor fibers, might influence the neighboring L4 nerve fibers and induce neurotrophin changes in the L4 DRG. We suggest that these changes of neurotrophins in the intact primary afferents of neighboring nerves may be one of many complex mechanisms, which can explain the abnormal pain behaviors after nerve injury. The ventral rhizotomy and ganglionectomy models may be useful to investigate the pathophysiological mechanisms of neuropathic pain after Wallerian degeneration in motor or sensory or mixed nerve.

Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models.

S Kaneko — 2008-02-12T16:50:55-00:00

J Neurosci, Vol. 26, No. 38. (20 September 2006), pp. 9794-9804.

Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named "Wallerian degeneration slow" (Wld(S)), can protect axons from degeneration, likely through a beta-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wld(S) mice showed a modest attenuation of behavioral deficits and axon loss, suggesting that EAE-associated axon damage may occur by a mechanism similar to Wallerian degeneration. Furthermore, nicotinamide (NAm), an NAD biosynthesis precursor, profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits in EAE models. Finally, we demonstrate that delayed NAm treatment is also beneficial to EAE models, pointing to the therapeutic potential of NAm as a protective agent for EAE and perhaps MS patients.

Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system.

RJ Watts — 2007-08-16T10:43:55-00:00

Neuron, Vol. 38, No. 6. (19 June 2003), pp. 871-885.

Axon pruning is widely used for the refinement of neural circuits in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neurodegenerative diseases. However, little is known about the cellular and molecular mechanisms of axon pruning. We use the stereotyped pruning of gamma neurons of the Drosophila mushroom bodies (MB) during metamorphosis to investigate these mechanisms. Detailed time course analyses indicate that MB axon pruning is mediated by local degeneration rather than retraction and that the disruption of the microtubule cytoskeleton precedes axon pruning. In addition, multiple lines of genetic evidence demonstrate an intrinsic role of the ubiquitin-proteasome system in axon pruning; for example, loss-of-function mutations of the ubiquitin activating enzyme (E1) or proteasome subunits in MB neurons block axon pruning. Our findings suggest that some forms of axon pruning during development may share similarities with degeneration of axons in response to injury.

Axonal Self-Destruction and Neurodegeneration

Martin Raff — 2007-12-04T22:16:22-00:00

Science, Vol. 296, No. 5569. (3 May 2002), pp. 868-871.

10.1126/science.1068613