CiteULike: psique's library [380 articles]

Purinergic signalling and disorders of the central nervous system

Geoffrey Burnstock — 2008-07-01T18:15:58-00:00

Nature Reviews Drug Discovery, Vol. 7, No. 7., pp. 575-590.

Creating and evaluating genetic tests predictive of drug response

Scott Weiss — 2008-07-01T18:15:58-00:00

Nature Reviews Drug Discovery, Vol. 7, No. 7. (20 June 2008), pp. 568-574.

Rapid strengthening of thalamo-amygdala synapses mediates cue–reward learning

Kay Tye — 2008-05-12T22:12:50-00:00

Nature (11 May 2008)

Assembly reflects evolution of protein complexes

Emmanuel Levy — 2008-06-19T16:48:31-00:00

Nature (18 June 2008)

Absolute requirement of GDNF for adult catecholaminergic neuron survival

Alberto Pascual — 2008-06-25T16:52:00-00:00

Nature Neuroscience, Vol. 11, No. 7. (08 June 2008), pp. 755-761.

Absolute requirement of GDNF for adult catecholaminergic neuron survival

A Pascual — 2005-01-20T00:29:54-00:00

Nature Neuroscience, Vol. 11 (2008), pp. 755-761.

GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.

Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients.

D Berg — 2008-06-20T09:53:20-00:00

Movement disorders : official journal of the Movement Disorder Society, Vol. 20, No. 9. (September 2005), pp. 1191-1194.

Data on the frequency of alpha-synuclein mutations in Parkinson's disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the alpha-synuclein gene are rare and suggest that other factors contribute to alpha-synuclein aggregation in the majority of PD patients.

Molecular landmarks along the axonal route: axonal transport in health and disease

Sara Salinas — 2008-06-15T20:30:37-00:00

Current Opinion in Cell Biology, Vol. In Press, Corrected Proof

Axonal transport of organelles has emerged as a key process in the regulation of neuronal differentiation and survival. Several components of this specialised transport machinery, their regulators and vesicular cargoes are mutated or altered in many neurodegenerative conditions. The molecular characterisation of these mechanisms has furthered our understanding of neuronal homeostasis, providing insights into the spatio-temporal control of membrane traffic and signalling in neurons with a precision not achievable in other cellular systems. Here, we summarise the recent advances in the field of axonal trafficking of different organelles, and the essential role of motor and adaptor proteins in this process.

Targeting the murine serotonin transporter: insights into human neurobiology

Dennis Murphy — 2008-01-22T06:15:29-00:00

Nature Reviews Neuroscience, Vol. 9, No. 2., pp. 85-96.

Neuroimaging and Depression: Current Status and Unresolved Issues

Gotlib — 2008-04-12T17:32:23-00:00

Current Directions in Psychological Science, Vol. 17, No. 2. (April 2008), pp. 159-163.

The Interface Between Neuroscience and Psychological Science

Poldrack — 2008-04-12T17:32:23-00:00

Current Directions in Psychological Science, Vol. 17, No. 2. (April 2008), pp. 61-61.

The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy.

JJ Shacka — 2008-06-12T20:02:19-00:00

Frontiers in bioscience : a journal and virtual library, Vol. 13 (2008), pp. 718-736.

Alterations in the autophagy-lysosomal degradation pathway have been described in normal brain aging and in age-related neurodegenerative diseases including Alzheimer's (AD) and Parkinson's (PD). An improper clearance of proteins in AD and PD may result either from a compromise in the autophagy-lysosomal degradation pathway or induce alterations in this pathway, and may result in neuron dysfunction and neuron loss. This review provides an overview of AD and PD with a specific focus on macroautophagy, chaperone-mediated autophagy and lysosome function in human and experimental models of AD and PD. Potential therapies for AD and PD are also discussed that may promote survival by regulating the autophagy and lysosomal degradation pathway.

Presynaptic receptors for dopamine, histamine, and serotonin.

TJ Feuerstein — 2008-06-12T19:57:05-00:00

Handbook of experimental pharmacology, No. 184. (2008), pp. 289-338.

Presynaptic receptors for dopamine, histamine and serotonin that are located on dopaminergic, histaminergic and sertonergic axon terminals, respectively, function as autoreceptors. Presynaptic receptors also occur as heteroreceptors on other axon terminals. Auto- and heteroreceptors mainly affect Ca(2+) -dependent exocytosis from the receptor-bearing nerve ending. Some additionally subserve other presynaptic functions.Presynaptic dopamine, histamine and serotonin receptors are involved in various (patho)physiological conditions. Examples are the following:Dopamine autoreceptors play a role in Parkinson's disease, schizophrenia and drug addiction. Dopamine heteroreceptors affecting the release of acetylcholine and of amino acid neurotransmitters in the basal ganglia are also relevant for Parkinson's disease. Peripheral dopamine heteroreceptors on postganglionic sympathetic terminals influence heart rate and vascular resistance through modulation of noradrenaline release.Blockade of histamine autoreceptors increases histamine synthesis and release and may support higher CNS functions such as arousal, cognition and learning. Peripheral histamine heteroreceptors on C fiber and on postganglionic sympathetic fiber terminals diminish neuropeptide and noradrenaline release, respectively. Both inhibititory effects are beneficial in myocardial ischemia. The inhibition of neuropeptide release also explains the antimigraine effects of some agonists of presynaptic histamine receptors.Upregulation of presynaptic serotonin autoreceptors is probably involved in the pathogenesis of major depression. Correspondingly, antidepressant treatments can be linked with a reduced density of 5-HT autoreceptors. 5-HT Heteroreceptor activation diminishes acetylcholine and GABA release and may therefore increase anxiety. In the periphery, presynaptic 5-HT heteroreceptor agonists shorten migraine attacks by inhibition of the release of neuropeptides from trigeminal afferents, apart from their constrictive action on meningeal vessels.

Mitochondria in the aetiology and pathogenesis of Parkinson's disease.

AH Schapira — 2008-06-12T18:21:32-00:00

Lancet neurology, Vol. 7, No. 1. (January 2008), pp. 97-109.

Several biochemical abnormalities have been described in the brains of patients with Parkinson's disease (PD), including oxidative stress and mitochondrial dysfunction. The identification of specific gene mutations that cause PD has reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and the sporadic forms of the disease. The proteins that are associated with familial PD--PTEN-induced putative kinase 1 (PINK1), DJ-1, alpha-synuclein, leucine-rich repeat kinase 2, and, possibly, parkin--are either mitochondrial proteins or are associated with mitochondria, and all interface with the pathways of oxidative stress and free radical damage. Insights into the aetiology and pathogenesis of PD provide hope that drugs or cocktails of drugs that might successfully intervene in the pathogenesis and slow the progression of the disease can be derived from the study of the converging rather than diverging pathways to cell dysfunction and death.

Protein folding, unfolding and misfolding: role played by intermediate States.

R Santucci — 2008-06-12T18:18:45-00:00

Mini reviews in medicinal chemistry, Vol. 8, No. 1. (January 2008), pp. 57-62.

Most proteins fold into their native structure through well defined pathways which involve a limited number of transient intermediates. Intermediates play a relevant role in the folding process; many diseases of genetic nature are in fact coupled with protein misfolding due to formation of stable, inactive intermediate species of the protein. This review deals with a number of diseases associated with protein misfolding and briefly describes the mechanism(s) responsible, at molecular level, for such pathologies. It is also considered the (native <--> molten globule) transition, recently observed for some proteins, in which a native protein converts into a stable compact intermediate state able to carry out distinct physiological functions inside the cell. A non-native compact form of cyt c, for example, appears to have a role in the programmed cell death (apoptosis) after that the protein is released from the mitochondrion, and non-native forms of the same protein appear involved in some of the disorders attributed to amyloid formation.

Cognitive impairment in Parkinson's disease and dementia with lewy bodies: a spectrum of disease.

R Goldmann Gross — 2008-06-12T18:13:52-00:00

Neuro-Signals, Vol. 16, No. 1. (2008), pp. 24-34.

Parkinson's disease (PD) is classically thought of as a movement disorder characterized by tremor, rigidity and postural instability. Nevertheless, there is growing recognition of prominent cognitive impairment in PD and related disorders, which is responsible for substantial disability in these patients. This review will focus on cognitive impairment associated with Lewy body pathology, including PD with dementia (PDD) and dementia with Lewy bodies (DLB). We will review the epidemiology, clinical evaluation, underlying mechanisms and treatment of cognitive impairment in these patients. Despite differences between PDD and DLB, there is clinical, neuropathological and radiological overlap between these disorders, supporting the view that they represent a spectrum of disease. These observations suggest that common targets for diagnosis and treatment of these disorders can be identified.

Mutations in LRRK2 as a cause of Parkinson's disease.

BI Giasson — 2008-06-12T18:11:53-00:00

Neuro-Signals, Vol. 16, No. 1. (2008), pp. 99-105.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of late-onset Parkinson's disease (PD). Clinical and pathological studies have demonstrated that in the majority of cases LRRK2 mutations lead to PD with classical clinical and pathological features. However, in some patients the pathological features can be distinct and/or more extensive than typically seen in PD. Collectively, these findings provide important clues into the mechanisms by which LRRK2 mutations can lead to demise of dopaminergic neurons. The understanding of LRRK2 protein function and its gene regulation and the consequences of mutations are still at their infancy, but scientific findings are progressing at a rapid pace. Although more detailed information on LRRK2 is still needed in the quest for therapeutic intervention that could halt or slow the progression of disease, here we summarize the current information on the biological and pathological properties of LRRK2.

Human-based studies on alpha-synuclein deposition and relationship to Parkinson's disease symptoms.

GM Halliday — 2008-06-12T18:02:34-00:00

Experimental neurology, Vol. 209, No. 1. (January 2008), pp. 12-21.

This article reviews the current knowledge on alpha-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of alpha-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. alpha-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of alpha-synuclein analysed, and antibody species used for the in situ detection of alpha-synuclein give variable results depending on the epitope visualised. Human studies show that alpha-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of alpha-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated alpha-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these alpha-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic alpha-synuclein and how to detect such differences in clinical situations.

In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson's disease?

MF Chesselet — 2008-06-12T18:01:11-00:00

Experimental neurology, Vol. 209, No. 1. (January 2008), pp. 22-27.

Mutations in alpha-synuclein were the first genetic defect linked to Parkinson's disease (PD). The relevance of alpha-synuclein to sporadic PD is strongly supported by the presence of alpha-synuclein aggregates in neurons of patients. This has prompted the development of numerous animal models based on alpha-synuclein overexpression, primarily through genetic methods in mice and viral transduction in rats. In mice, different promoters and transgenes lead to a wide variety of phenotypes accompanied by non-existent, late onset, or non-specific neurodegeneration. Rapid neurodegeneration, in contrast, is observed after viral transduction but is limited to the targeted region and does not mimic the broad pathology observed in the disease. Overall, each model reproduces a subset of features of PD and can be used to identify therapeutic targets and test disease-modifying therapies. The predictive value of all models of the disease, however, remains speculative in the absence of effective neuroprotective treatments for PD in humans.

Oxidative stress and neurotoxicity.

LM Sayre — 2008-06-12T17:56:48-00:00

Chemical research in toxicology, Vol. 21, No. 1. (January 2008), pp. 172-188.

There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.

The blood-brain barrier in health and chronic neurodegenerative disorders.

BV Zlokovic — 2008-01-28T16:03:29-00:00

Neuron, Vol. 57, No. 2. (24 January 2008), pp. 178-201.

The blood-brain barrier (BBB) is a highly specialized brain endothelial structure of the fully differentiated neurovascular system. In concert with pericytes, astrocytes, and microglia, the BBB separates components of the circulating blood from neurons. Moreover, the BBB maintains the chemical composition of the neuronal "milieu," which is required for proper functioning of neuronal circuits, synaptic transmission, synaptic remodeling, angiogenesis, and neurogenesis in the adult brain. BBB breakdown, due to disruption of the tight junctions, altered transport of molecules between blood and brain and brain and blood, aberrant angiogenesis, vessel regression, brain hypoperfusion, and inflammatory responses, may initiate and/or contribute to a "vicious circle" of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others. These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the BBB and other nonneuronal cells of the neurovascular unit.

Principles and practical issues for cryopreservation of nerve cells.

SJ Paynter — 2008-06-12T17:49:25-00:00

Brain research bulletin, Vol. 75, No. 1. (31 January 2008), pp. 1-14.

Nerve cells isolated from the brain have a number of research and clinical applications, not the least of which is their transplantation to patients with Parkinson's disease. Neural primary and precursor cells of several areas of the brain are potential candidates for transplantation and research. However, supply of suitable tissue is one of the major problems associated with the widespread application of such techniques. The ability to store such tissue for prolonged periods would greatly alleviate this problem. Cryopreservation allows indefinite storage, provided the storage temperature is sufficiently low. Whilst many of the potentially usable cell types have been shown to be capable of surviving cryopreservation to some degree, survival post-thaw needs to be considerably improved. Cryopreservation techniques applied to date are mostly crude and often adopted from those used for unrelated cell types. Studies involving cryopreservation of primary neural cells and stem cells are reviewed, the basic principles of cryopreservation explained and suggestions made for improvements to the low temperature storage of these cells.

Programmed cell death and new discoveries in the genetics of parkinsonism

Burke — 2008-01-31T12:32:07-00:00

Journal of Neurochemistry, Vol. 104, No. 4. (February 2008), pp. 875-890.

Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?

Thompson — 2008-01-07T17:30:23-00:00

Genes, Brain & Behavior, Vol. 7, No. s1. (February 2008), pp. 28-42.

[The role for oxidative stress in neurodegenerative diseases]

N Shibata — 2008-06-12T17:39:29-00:00

Brain and nerve = Shinkei kenkyū no shinpo, Vol. 60, No. 2. (February 2008), pp. 157-170.

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.

Mechanisms and Functional Implications of Adult Neurogenesis

Chunmei Zhao — 2008-02-26T14:22:06-00:00

Cell, Vol. 132, No. 4. (22 February 2008), pp. 645-660.

The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. In this review, we discuss the factors that regulate proliferation and fate determination of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

A mid-life crisis for aging theory

Ken Garber — 2008-04-08T04:45:37-00:00

Nature Biotechnology, Vol. 26, No. 4., pp. 371-374.

Open-source science to enable drug discovery

Aled Edwards — 2008-06-12T09:51:18-00:00

Drug Discovery Today, Vol. In Press, Corrected Proof

Alpha-synuclein haplotypes implicated in risk of Parkinson's disease.

EK Tan — 2008-06-11T21:26:37-00:00

Neurology, Vol. 62, No. 1. (13 January 2004), pp. 128-131.

The authors examined four- and six-loci haplotype constructs (from five single nucleotide polymorphisms and three microsatellite regions) of the alpha-synuclein gene in patients with Parkinson's disease (PD) and controls in an ethnic Chinese population. Logistic regression analysis demonstrated an association of NACP-Rep1 (p = 0.002) and L478 (p < 0.0001) with risk of PD after correction for the effects of age, sex, and the other polymorphic loci. Specific four-loci and six-loci haplotypes were significantly associated with an increased or decreased risk of PD.

Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.

DM Maraganore — 2008-06-11T21:14:29-00:00

JAMA : the journal of the American Medical Association, Vol. 296, No. 6. (9 August 2006), pp. 661-670.

CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). CONCLUSION: This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

alpha-Synuclein promoter confers susceptibility to Parkinson's disease.

P Pals — 2008-06-11T21:09:50-00:00

Annals of neurology, Vol. 56, No. 4. (October 2004), pp. 591-595.

Familial Parkinson's disease (PD) has been linked to missense and genomic multiplication mutations of the alpha-synuclein gene (SNCA). Genetic variability within SNCA has been implicated in idiopathic PD in many populations. We now confirm and extend these findings, within a Belgian sample, using a high-resolution map of genetic markers across the SNCA locus. Our study implicates the SNCA promoter in susceptibility to PD, and more specifically defines a minimum promoter haplotype, spanning approximately 15.3kb of sequence, which is overrepresented in patients. Our findings represent a biomarker for PD and may have implications for patient diagnosis, longitudinal evaluation, and treatment.

Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy.

KA Conway — 2008-06-11T20:06:15-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 2. (18 January 2000), pp. 571-576.

The Parkinson's disease (PD) substantia nigra is characterized by the presence of Lewy bodies containing fibrillar alpha-synuclein. Early-onset PD has been linked to two point mutations in the gene that encodes alpha-synuclein, suggesting that disease may arise from accelerated fibrillization. However, the identity of the pathogenic species and its relationship to the alpha-synuclein fibril has not been elucidated. In this in vitro study, the rates of disappearance of monomeric alpha-synuclein and appearance of fibrillar alpha-synuclein were compared for the wild-type (WT) and two mutant proteins, as well as equimolar mixtures that may model the heterozygous PD patients. Whereas one of the mutant proteins (A53T) and an equimolar mixture of A53T and WT fibrillized more rapidly than WT alpha-synuclein, the other (A30P) and the corresponding equimolar mixture with WT fibrillized more slowly. However, under conditions that ultimately produced fibrils, the A30P monomer was consumed at a comparable rate or slightly more rapidly than the WT monomer, whereas A53T was consumed even more rapidly. The difference between these trends suggested the existence of nonfibrillar alpha-synuclein oligomers, some of which were separated from fibrillar and monomeric alpha-synuclein by sedimentation followed by gel-filtration chromatography. Spheres (range of heights: 2-6 nm), chains of spheres (protofibrils), and rings resembling circularized protofibrils (height: ca. 4 nm) were distinguished from fibrils (height: ca. 8 nm) by atomic force microscopy. Importantly, drug candidates that inhibit alpha-synuclein fibrillization but do not block its oligomerization could mimic the A30P mutation and thus may accelerate disease progression.

A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders.

VN Uversky — 2008-06-11T19:39:18-00:00

Journal of biomolecular structure & dynamics, Vol. 21, No. 2. (October 2003), pp. 211-234.

Under the physiological conditions in vitro, alpha-synuclein, a conservative presynaptic protein, the aggregation and fibrillation of which is assumed to be involved into the pathogenesis of Parkinson's disease and several other neurodegenerative disorders, known as synucleinopathies, is characterized by the lack of rigid well-defined structure; i.e., it belongs to the class of intrinsically unstructured proteins. Intriguingly, alpha-synuclein is characterized by a remarkable conformational plasticity, adopting a series of different conformations depending on the environment. For example, this protein may either stay substantially unfolded, or adopt an amyloidogenic partially folded conformation, or fold into alpha-helical or beta-structural species, both monomeric and oligomeric. Furthermore, it might form several morphologically different types of aggregates, including oligomers (spheres or doughnuts), amorphous aggregates, and or amyloid-like fibrils. The peculiarities of this astonishing conformational behavior are analyzed to shed light on structural plasticity of this protein-chameleon.

Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.

E Masliah — 2008-06-11T19:34:01-00:00

Science (New York, N.Y.), Vol. 287, No. 5456. (18 February 2000), pp. 1265-1269.

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein.

SM Fleming — 2008-06-11T19:18:46-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 24, No. 42. (20 October 2004), pp. 9434-9440.

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

A phosphatase cascade by which rewarding stimuli control nucleosomal response

Alexandre Stipanovich — 2008-05-22T01:22:13-00:00

Nature (21 May 2008)

How stem cells age and why this makes us grow old

Norman Sharpless — 2007-08-24T11:06:23-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 9., pp. 703-713.

Prediction of Interacting Single-Stranded RNA Bases by Protein-Binding Patterns

Alexandra Shulman-Peleg — 2008-06-03T06:08:01-00:00

Journal of Molecular Biology, Vol. 379, No. 2. (29 May 2008), pp. 299-316.

Prediction of protein-RNA interactions at the atomic level of detail is crucial for our ability to understand and interfere with processes such as gene expression and regulation. Here, we investigate protein binding pockets that accommodate extruded nucleotides not involved in RNA base pairing. We observed that most of the protein-interacting nucleotides are part of a consecutive fragment of at least two nucleotides whose rings have significant interactions with the protein. Many of these share the same protein binding cavity and more than 30% of such pairs are [pi]-stacked. Since these local geometries cannot be inferred from the nucleotide identities, we present a novel framework for their prediction from the properties of protein binding sites. First, we present a classification of known RNA nucleotide and dinucleotide protein binding sites and identify the common types of shared 3-D physicochemical binding patterns. These are recognized by a new classification methodology that is based on spatial multiple alignment. The shared patterns reveal novel similarities between dinucleotide binding sites of proteins with different overall sequences, folds and functions. Given a protein structure, we use these patterns for the prediction of its RNA dinucleotide binding sites. Based on the binding modes of these nucleotides, we further predict an RNA fragment that interacts with those protein binding sites. With these knowledge-based predictions, we construct an RNA fragment that can have a previously unknown sequence and structure. In addition, we provide a drug design application in which the database of all known small-molecule binding sites is searched for regions similar to nucleotide and dinucleotide binding patterns, suggesting new fragments and scaffolds that can target them.

Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: Future therapeutic targets

Aletta Kraneveld — 2008-06-10T21:17:51-00:00

European Journal of Pharmacology, Vol. 585, No. 2-3. (13 May 2008), pp. 361-374.

The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory bowel disease and irritable bowel syndrome. Since both disorders are associated with increased immune cell numbers, nerve growth and activation of both immune cells and nerves, we focus in this review on the involvement of immune cell-nerve interactions in inflammatory bowel disease and irritable bowel syndrome. Firstly, the possible effects of enteric nerves, especially of the nonadrenergic and noncholinergic nerves, on the intestinal immune system and their possible role in the pathogenesis of chronic intestinal inflammatory diseases are described. Secondly, the possible effects of immunological factors, from the innate (chemokines and Toll-like receptors) as well as the adaptive (cytokines and immunoglobulins) immune system, on gastro-intestinal nerves and its potential role in the development of inflammatory bowel disease and irritable bowel syndrome are reviewed. Investigations of receptor-mediated and intracellular signal pathways in neuro-immune interactions might help to develop more effective therapeutic approaches for chronic inflammatory intestinal diseases.

Sensitivity to Oxidative Stress in DJ-1-Deficient Dopamine Neurons: An ES- Derived Cell Model of Primary Parkinsonism

Cecile Martinat — 2008-06-10T19:23:49-00:00

PLoS Biology, Vol. 2, No. 11. (1 November 2004), e327.

The hallmark of Parkinson's disease (PD) is the selective loss of dopamine neurons in the ventral midbrain. Although the cause of neurodegeneration in PD is unknown, a Mendelian inheritance pattern is observed in rare cases, indicating a genetic factor. Furthermore, pathological analyses of PD substantia nigra have correlated cellular oxidative stress and altered proteasomal function with PD. Homozygous mutations in DJ-1 were recently described in two families with autosomal recessive Parkinsonism, one of which is a large deletion that is likely to lead to loss of function. Here we show that embryonic stem cells deficient in DJ-1 display increased sensitivity to oxidative stress and proteasomal inhibition. The accumulation of reactive oxygen species in toxin-treated DJ-1-deficient cells initially appears normal, but these cells are unable to cope with the consequent damage that ultimately leads to apoptotic death. Furthermore, we find that dopamine neurons derived from in vitro–differentiated DJ-1-deficient embryonic stem cells display decreased survival and increased sensitivity to oxidative stress. These data are consistent with a protective role for DJ-1, and demonstrate the utility of genetically modified embryonic stem cell–derived neurons as cellular models of neuronal disorders.

DJ-1 Is a Redox-Dependent Molecular Chaperone That Inhibits α-Synuclein Aggregate Formation

Shoshana Shendelman — 2008-06-10T19:22:27-00:00

PLoS Biology, Vol. 2, No. 11. (1 November 2004), e362.

Parkinson's disease (PD) pathology is characterized by the degeneration of midbrain dopamine neurons (DNs) ultimately leading to a progressive movement disorder in patients. The etiology of DN loss in sporadic PD is unknown, although it is hypothesized that aberrant protein aggregation and cellular oxidative stress may promote DN degeneration. Homozygous mutations in DJ-1 were recently described in two families with autosomal recessive inherited PD (Bonifati et al. 2003). In a companion article (Martinat et al. 2004), we show that mutations in DJ-1 alter the cellular response to oxidative stress and proteasomal inhibition. Here we show that DJ-1 functions as a redox-sensitive molecular chaperone that is activated in an oxidative cytoplasmic environment. We further demonstrate that DJ-1 chaperone activity in vivo extends to α-synuclein, a protein implicated in PD pathogenesis.

A New Cell Model for Parkinson's Disease

2008-06-10T19:19:01-00:00

PLoS Biology, Vol. 2, No. 11. (1 November 2004), e385.

Conformational Equilibria in Monomeric α-Synuclein at the Single-Molecule Level

Massimo Sandal — 2008-06-10T18:48:00-00:00

PLoS Biology, Vol. 6, No. 1. (1 January 2008), e6.

Human α-Synuclein (αSyn) is a natively unfolded protein whose aggregation into amyloid fibrils is involved in the pathology of Parkinson disease. A full comprehension of the structure and dynamics of early intermediates leading to the aggregated states is an unsolved problem of essential importance to researchers attempting to decipher the molecular mechanisms of αSyn aggregation and formation of fibrils. Traditional bulk techniques used so far to solve this problem point to a direct correlation between αSyn's unique conformational properties and its propensity to aggregate, but these techniques can only provide ensemble-averaged information for monomers and oligomers alike. They therefore cannot characterize the full complexity of the conformational equilibria that trigger the aggregation process. We applied atomic force microscopy–based single-molecule mechanical unfolding methodology to study the conformational equilibrium of human wild-type and mutant αSyn. The conformational heterogeneity of monomeric αSyn was characterized at the single-molecule level. Three main classes of conformations, including disordered and “β-like” structures, were directly observed and quantified without any interference from oligomeric soluble forms. The relative abundance of the “β-like” structures significantly increased in different conditions promoting the aggregation of αSyn: the presence of Cu2+, the pathogenic A30P mutation, and high ionic strength. This methodology can explore the full conformational space of a protein at the single-molecule level, detecting even poorly populated conformers and measuring their distribution in a variety of biologically important conditions. To the best of our knowledge, we present for the first time evidence of a conformational equilibrium that controls the population of a specific class of monomeric αSyn conformers, positively correlated with conditions known to promote the formation of aggregates. A new tool is thus made available to test directly the influence of mutations and pharmacological strategies on the conformational equilibrium of monomeric αSyn.

Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model of Parkinson's disease

Smith — 2008-04-15T16:32:08-00:00

European Journal of Neuroscience, Vol. 27, No. 8. (April 2008), pp. 2133-2146.

The [alpha]-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease

Patrick Mcgeer — 2008-06-04T17:20:45-00:00

Experimental Neurology, Vol. In Press, Corrected Proof

Altered vesicular dopamine storage in Parkinson's disease: a premature demise

Michael Caudle — 2008-06-04T16:56:02-00:00

Trends in Neurosciences, Vol. 31, No. 6. (June 2008), pp. 303-308.

Dopamine is a potentially toxic neurotransmitter that has long been speculated to contribute to the pathogenesis of Parkinson's disease (PD). Recent work has demonstrated the importance of proper storage of dopamine in vesicles to maintain dopamine homeostasis, thus protecting neurons from the detrimental effects of dopamine accumulation and breakdown in the cytosol. These studies suggest that factors which affect dopamine storage might increase the susceptibility of dopamine neurons to further environmental or genetic insults, exacerbating the neuronal degeneration that characterizes PD. This review seeks to revisit the pathogenicity of cytosolic dopamine and further address the critical role of neurotransmitter storage in dopamine-mediated neurotoxicity.

Parkinson's disease and pesticides: a toxicological perspective

Jaime Hatcher — 2008-06-04T16:54:29-00:00

Trends in Pharmacological Sciences, Vol. 29, No. 6. (June 2008), pp. 322-329.

Environmental factors have been shown to contribute to the incidence of Parkinson's disease (PD). Pesticides, which represent one of the primary classes of environmental agents associated with PD, share the common feature of being intentionally released into the environment to control or eliminate pests. Pesticides consist of multiple classes and subclasses of insecticides, herbicides, rodenticides, fungicides, fumigants and others and exhibit a vast array of chemically diverse structures. In this review we examine the evidence regarding the ability of each of the major pesticide subclasses to increase the incidence of PD. We propose that, from a toxicological perspective, it would be beneficial to identify specific subclasses, common structural features and the propensity for widespread human exposure when considering the potential role in PD, rather than using the overly broad term of [`]pesticides' to describe this diverse group of chemicals. Furthermore, these chemicals and their environmentally relevant combinations should be evaluated for their ability to promote or accelerate PD and not merely for being singular causative agents.

Alpha-Synuclein and Parkinson's Disease

2008-06-03T18:16:37-00:00

(August 2001)

Alpha-Synuclein and Parkinson's Disease Proteins carry out many crucial functions in the body and brain. Researchers, however, are finding out that some have a sinister side. Recent studies indicate that negative influences can turn the protein, alpha-synuclein, into a major contributor of the movement-impairing disorder, Parkinson's disease. The insights may lead to new ways to treat the brain disease as well as other related ailments. A protein inside the brain, dubbed alpha-synuclein, lives a Dr. Jekyll and Mr. Hyde existence. Normally, alpha-synuclein (AS) aids brain function, possibly by helping cells communicate with one another. Recent studies, however, show that certain forces negatively influence the protein, allowing Mr. Hyde a turn on stage. This "evil" AS appears to contribute to the development of the brain disorder, Parkinson's disease, which harms the movement of more than one million Americans. The new insights into the protein's sinister side are leading to: * A clearer understanding of the precise role AS plays in normal brain function and disease. * Innovative ways to protect the brain from harmful AS and potentially treat Parkinson's disease as well as related brain disorders. Patients with Parkinson's disease experience a variety of movement problems that get worse over time. Symptoms include trembling, stiffness of the limbs and poor balance, among others. For years, researchers have known that the impairments result from a loss of cells in the brain that produce the chemical dopamine and relay movement signals. A mystery, however, remained: What launches the cell destruction? Starting in the late 1990s evidence began to implicate AS. Researchers examined the genes passed down through the generations of several families with high incidences of Parkinson's disease. A gene that regulates the production of AS turned out to be faulty. Furthermore, scientists analyzed dense deposits commonly found in the brain cells of patients with a family history of the disease as well as patients with little or no signs of a family link. They found that AS is the main component of the deposits (see images). These discoveries led many to speculate that certain influences, such as a defective gene or environmental trigger, can propel AS to turn toxic. As Mr. Hyde, the protein may abnormally clump up, form the clogging deposits and eventually choke the dopamine cells to death. More recently, by breeding mice and fruit flies that contained human versions of the AS gene, researchers confirmed that AS has a dastardly side. Insects genetically altered to include the same faulty AS genes found in the Parkinson's-plagued families developed brain deposits and movement problems as they aged. Furthermore, some of their dopamine cells died. In mice, the faulty AS genes also triggered some signs of Parkinson-type problems. In addition, scientists discovered that flies and mice bred with a normal version of the human gene developed some signs of Parkinson's. They now are trying to better understand how the AS produced by this normal human gene may turn toxic. Possibly the human gene produces an excess amount of AS in the insects and animals, which creates the detrimental effects. This idea is bolstered by recent research that showed high AS-producing mice have significantly more brain deposits than low producers. Scientists also are investigating how specific environmental factors may help push AS down a negative path. One recent study found that when rats received steady amounts of the common pesticide, rotenone, into their blood they developed evidence of AS-packed deposits in their brain tissue and other common signs of Parkinson's disease, such as movement problems and a degeneration of dopamine cells. Researchers suspect that exposure to certain factors in normal living, such as the pesticide, may set off internal chemical reactions that produce a glut of unstable free radicals in the brain. These notoriously destructive molecules possibly latch onto AS and create intense havoc. Supporting this idea, a recent study found the AS in Parkinson's brain deposits has free radical damage. As a next step, researchers plan to uncover the exact dynamic between AS and all these other players. Another goal is to find ways to interfere with the toxic AS process and hopefully say goodbye to Mr. Hyde and Parkinson's disease. Small, dense deposits, termed Lewy bodies or Lewy neurites, stud the brains of patients with Parkinson's disease. The three sections of brain tissue shown above depict how the protein, alpha-synuclein (stained brown), packs these deposits. This finding, and others, leads many scientists to believe that alpha-synuclein plays a key role in Parkinson's disease. Researchers are now searching for ways to stop their negative actions and hopefully aid patients in the future.

Alpha-synuclein: normal function and role in neurodegenerative diseases.

EH Norris — 2008-06-03T18:14:54-00:00

Current topics in developmental biology, Vol. 60 (2004), pp. 17-54.

Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Since their discovery and characterization during the last decade, much has been learned about their structure, potential functions, interactions with other proteins, and roles in disease. One of these proteins, alpha-synuclein (alpha-syn), is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Furthermore, genetic and biological studies support a role for alpha-syn in the pathophysiology of these diseases. Therefore, research must be continued in order to better understand the functions of the synuclein proteins under normal physiological conditions as well as their role in diseases.

Developmental expression of [alpha]-synuclein in rat hippocampus and cerebral cortex

K Petersen — 2008-06-03T18:14:28-00:00

Neuroscience, Vol. 91, No. 2. (June 1999), pp. 651-659.

[alpha]-Synuclein is an evolutionary highly conserved neuronal protein localized in presynaptic nerve terminals. The protein has been suggested to be involved in the pathogenesis of neurodegenerative diseases, but little is known about the physiological function of the protein. In the present study we used newborn, three, 14, 93 and 710-day-old rats to examine the expression of [alpha]-synuclein messenger RNA and protein during development of the hippocampus and cerebral cortex. Using in situ hybridization and an S1 nuclease protection assay, we found a high expression of [alpha]-synuclein messenger RNA during early postnatal development, followed by a marked decrease between postnatal days 14 and 93. In contrast, the amount of [alpha]-synuclein protein, as determined by immunoblotting, continued to increase throughout development and remained at a high level for at least two years. The persistent high expression of [alpha]-synuclein protein throughout development suggests that the protein is involved in maintaining synaptic function. Furthermore, the discrepancy between the levels of [alpha]-synuclein messenger RNA and protein after postnatal day 14 indicates that the amount of [alpha]-synuclein is determined by post-transcriptional regulation, and not by messenger RNA expression alone. To estimate the changes of [alpha]-synuclein expression per synapse, we compared the developmental expression of [alpha]-synuclein with synaptophysin, a well-established synaptic marker. The [alpha]-synuclein/synaptophysin messenger RNA and protein ratio was high during early development, but low in adult (postnatal day 93) and old (postnatal day 710) rats. This could indicate a higher expression of [alpha]-synuclein per synapse during early development.