CiteULike: Group: GeschwindLab - library [608 articles]

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance

Sophie Brouard — 2007-09-15T15:11:42-00:00

Proceedings of the National Academy of Sciences (14 September 2007), 0705834104.

Communicated by Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France, July 2, 2007 (received for review October 11, 2006)Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted. 10.1073/pnas.0705834104

Drug Insight: effects mediated by peroxisome proliferator-activated receptor-[gamma] in CNS disorders

Michael Heneka — 2007-09-12T01:47:11-00:00

Nat Clin Pract Neuro, Vol. 3, No. 9. (2007), pp. 496-504.

Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood

Heike Runne — 2007-09-12T01:06:25-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 36. (4 September 2007), pp. 14424-14429.

Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:1102311028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies. 10.1073/pnas.0703652104

Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial.

Nicholas A Di Prospero — 2007-09-11T21:03:31-00:00

Lancet Neurol (6 September 2007)

BACKGROUND: Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown. METHODS: 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone ( approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632. FINDINGS: Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores. INTERPRETATION: Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.

Linking mitochondrial function to diabetes mellitus: an animal's tale

Carolyn Berdanier — 2007-09-11T20:21:19-00:00

Am J Physiol Cell Physiol, Vol. 293, No. 3. (1 September 2007), pp. C830-836.

Diabetes mellitus is one of the most common genetic diseases that afflicts humans. It is not a single disease but a collection of diseases having in common an abnormal glucose-insulin relationship and a dysfunctional regulation of glucose homeostasis. Of interest is the diabetic state that results when the mitochondrial genome mutates. Epidemiological studies have shown this to occur in humans. Detailed metabolic studies that are impossible to conduct in humans have been carried out in the BHE/Cdb rat. This rat has a mutated mitochondrial ATPase 6 gene. Strategies to ameliorate the consequences of this mutation have been explored and some of the mechanisms for the transcription and translation of the mitochondrial gene product have been elucidated. 10.1152/ajpcell.00227.2006

Deconvolution of the cellular oxidative stress response with organelle-specific Peptide conjugates.

KP Mahon — 2007-09-11T16:38:44-00:00

Chem Biol, Vol. 14, No. 8. (August 2007), pp. 923-930.

Oxidative stress is a deleterious force that must be combated relentlessly by aerobic organisms and is known to underlie many human diseases including atherosclerosis, Parkinson's disease, and Alzheimer's disease. Information available about the oxidative stress response has come primarily from studies using reactive oxygen species (ROS) with ill-defined locations within the cell. Thus, existing models do not account for possible differences between stress originating within particular regions of the cell. Here, oxidative stress is studied at the subcellular level using ROS-generating compounds localizing within two different organelles: the nucleus and the mitochondrion. Differences in cytotoxicity, gene expression, and survival pathway activation are detected as a function of the subcellular origin of oxidative stress, indicating that independent mechanisms are used to cope with oxidative stress arising in different cellular compartments. These comparative studies, enabled by the development of organelle-specific oxidants, examine the cellular responses to site-specific oxidative stress with heightened precision.

The genetics of frontotemporal lobar degeneration.

R Rademakers — 2007-09-11T02:52:15-00:00

Curr Neurol Neurosci Rep, Vol. 7, No. 5. (September 2007), pp. 434-442.

The clinical disorders associated with frontotemporal lobar degeneration (FTLD) are increasingly recognized as an important cause of early-onset dementia. Patients usually present with progressive changes in personality, behavior, or language, progressing to general cognitive impairment and ultimately death. In the past decade, improved clinical and histopathologic characterization uncovered extensive heterogeneity, and multiple clinical and pathologic FTLD subtypes were defined. Simultaneously, the discovery of four causal FTLD genes emphasized the genetic complexity associated with FTLD. More recently, the field of FTLD has gained increased attention as a result of two major findings. First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS). In this report, we outline the progress made in the study of the genetic etiologies and neuropathologic substrates in FTLD.

Clearance of amyloid-β by circulating lipoprotein receptors

Abhay Sagare — 2007-09-08T22:04:49-00:00

Nature Medicine, Vol. 13, No. 9. (12 August 2007), pp. 1029-1031.

The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments.

Ian Mackenzie — 2007-09-11T00:19:29-00:00

Neurogenetics (6 September 2007)

The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of frontotemporal lobar degeneration (FTLD). Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD. FTLD with tau-negative, ubiquitinated inclusions (FTLD-U) is now recognized as the most common pathology associated with clinical FTLD. Mutations in the progranulin gene (PGRN) have been identified as the cause of FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause FTLD by reducing the amount of functional PGRN protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U. The ubiquitinated pathological protein in FTLD-U has been identified as TAR deoxyribonucleic acid-binding protein with M (r) 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and therapeutics.

DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase

Eva Andres-Mateos — 2007-09-10T21:42:32-00:00

Proceedings of the National Academy of Sciences (31 August 2007), 0703219104.

Edited by Solomon H. Snyder, Johns Hopkins University, Baltimore, MD, and approved July 30, 2007 (received for review April 7, 2007)Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H2O2 indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H2O2. DJ-1 KO mice of 23 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H2O2 through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H2O2 due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase. 10.1073/pnas.0703219104

SUT-1 enables tau-induced neurotoxicity in C. elegans

Brian Kraemer — 2007-09-10T19:38:10-00:00

Hum. Mol. Genet., Vol. 16, No. 16. (15 August 2007), pp. 1959-1971.

We previously reported a transgenic Caenorhabditis elegans model for tauopathies in which expression of human tau in neurons caused insoluble phosphorylated tau accumulation, neurodegeneration and uncoordinated movement (Unc). To identify genes participating in tau neurotoxicity, we conducted a forward genetic screen for mutations that ameliorate tau-induced uncoordination. The recessive mutation sut-1(bk79) partially suppresses the Unc phenotype, tau aggregation and neurodegenerative changes caused by tau. We identified the sut-1 gene and found it encodes a novel protein. We conducted a yeast two hybrid screen to identify SUT-1 binding partners and found UNC-34, the C. elegans homolog of the cytoskeletal regulatory protein Enabled (ENA). In vitro protein binding assays and genetic studies validated the interaction between SUT-1 and UNC-34. The SUT-1/UNC-34 proteinprotein interaction plays a role in both the normal function of UNC-34 and in the tau-induced phenotype. Thus, we have found a conserved molecular pathway participating in tau neurotoxicity in C. elegans. 10.1093/hmg/ddm143

Inhibitors of metabolism rescue cell death in Huntington's disease models

Hemant Varma — 2007-09-10T19:08:57-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 36. (4 September 2007), pp. 14525-14530.

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder. HD is caused by polyglutamine expansions in the huntingtin (htt) protein that result in neuronal loss and contribute to HD pathology. The mechanisms of neuronal loss in HD are elusive, and there is no therapy to alleviate HD. To find small molecules that slow neuronal loss in HD, we screened 1,040 biologically active molecules to identify suppressors of cell death in a neuronal cell culture model of HD. We found that inhibitors of mitochondrial function or glycolysis rescued cell death in this cell culture and in in vivo HD models. These inhibitors prevented cell death by activating prosurvival ERK and AKT signaling but without altering cellular ATP levels. ERK and AKT inhibition through the use of specific chemical inhibitors abrogated the rescue, whereas their activation through the use of growth factors rescued cell death, suggesting that this activation could explain the protective effect of metabolic inhibitors. Both ERK and AKT signaling are disrupted in HD, and activating these pathways is protective in several HD models. Our results reveal a mechanism for activating prosurvival signaling that could be exploited for treating HD and possibly other neurodegenerative disorders. 10.1073/pnas.0704482104

Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains.

Martin Ingelsson — 2007-08-28T20:31:46-00:00

Acta Neuropathol (Berl) (25 August 2007)

Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer's disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.

Expression, localization and Tau Exon 10 splicing activity of the brain RNA-binding protein TNRC4

Paul Chapple — 2007-08-28T15:18:55-00:00

Hum. Mol. Genet. (28 August 2007), ddm233.

Elucidating the mechanisms of alternative splicing in the brain is a prerequisite to the understanding of the pathogenesis of major neurological diseases linked to impairment of pre-mRNA alternative splicing. The gene Trinucleotide Repeat Containing 4 (TNRC4) is predicted to encode a member of the CELF (CUG-BP- and ETR-3-like factors) family of RNA-binding proteins containing a 15-18 residues polyglutamine sequence. The TNRC4 transcript is selectively expressed in the brain. Using an anti-peptide antibody against the predicted sequence, we establish the presence of TNRC4 as a [~]50 kDa protein in the brain. Full-length TNRC4 displays nuclear and cytoplasmic localizations in transfected cells whereas a C-terminally truncated mutant is essentially confined to the cytoplasm. TNRC4 is not recruited into inclusions formed by polyglutamine expanded ataxin-1 or huntingtin. TNRC4 activates tau exon 10 (E10) inclusion at high efficiency in transfected cells. TNRC4 contains two consecutive N-terminal RNA recognition motifs (RRM) separated from the C-terminal RRM. Deletion and point mutant analysis shows that the activity of TNRC4 on tau E10 splicing is mainly mediated by the RNA-binding activity of the second RRM and involves an intronic element of the tau pre-mRNA. The polyglutamine sequence has no effect on the activity of TNRC4 on tau E10 splicing. This study represents the first characterization of TNRC4 and provides further insight into the mechanisms of brain-specific alternative splicing and their possible pathological implications. 10.1093/hmg/ddm233

Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's Disease

Marian Hamshere — 2007-08-28T15:17:59-00:00

Hum. Mol. Genet. (27 August 2007), ddm224.

Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs. Multipoint, model-free affected relative pair linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with a LOD score > 1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosomes 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2. 10.1093/hmg/ddm224

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Hirokazu Fukui — 2007-08-22T15:17:48-00:00

PNAS (21 August 2007), 0705738104.

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved July 20, 2007 (received for review June 19, 2007)Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the age-dependent accumulation of beta-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of beta-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COX-deficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKIIalpha promoter-driven Cre-recombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in Abeta42 level, beta-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments. 10.1073/pnas.0705738104

Tau-mediated neurodegeneration in Alzheimer's disease and related disorders

Carlo Ballatore — 2007-08-20T14:22:36-00:00

Nat Rev Neurosci, Vol. 8, No. 9. (2007), pp. 663-672.

Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin.

Sylvia Boesch — 2007-08-20T01:29:17-00:00

Ann Neurol (13 August 2007)

To determine the role of recombinant human erythropoietin as a possible treatment option in Friedreich's ataxia, we performed an open-label clinical pilot study. Primary outcome measure was the change of frataxin levels at week 8 versus baseline. Twelve Friedreich's ataxia patients received 5,000 units recombinant human erythropoietin three times weekly subcutaneously. Frataxin levels were measured in isolated lymphocytes by enzyme-linked immunosorbent assay. In addition, urinary 8-hydroxydeoxyguanosine and serum peroxides, were measured. Treatment with recombinant human erythropoietin showed a persistent and significant increase in frataxin levels after 8 weeks (p < 0.01). All patients showed a reduction of oxidative stress markers. Ann Neurol 2007.

Oligodendrocytes from neural stem cells express alpha-synuclein: increased numbers from presenilin 1 deficient mice.

JG Culvenor — 2007-07-31T01:47:33-00:00

Neuroreport, Vol. 13, No. 10. (19 July 2002), pp. 1305-1308.

alpha-Synuclein normally a synaptic vesicle-associated cytoplasmic protein is the major component of filamentous inclusions of neurons in Parkinson's disease and dementia with Lewy bodies. It is also the major component of glial inclusions of multiple system atrophy. In characterizing cells derived from embryonic neural stem cells we found all oligodendrocytes had strong cytoplasmic expression of alpha-synuclein. Comparison of cells from presenilin 1 (PS1)-deficient mice with wild type revealed a 7-fold increase in oligodendrocytes. Western blotting analysis indicated the cells contained alpha-synuclein monomers and SDS-stable dimers and trimers. This cell system of oligodendroglial alpha-synuclein expression is a useful system to study alpha-synuclein metabolism in the cell type affected in multiple system atrophy. Increased oligodendroglial cell numbers from PS1-deficient cells provides further evidence for a role of PS1-dependent Notch signalling in cell fate decisions.

Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.

DR Borchelt — 2007-07-24T21:53:28-00:00

Neuron, Vol. 17, No. 5. (November 1996), pp. 1005-1013.

Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Abeta1-42(43)/Abeta1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Abeta1-42(43)/Abeta1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Abeta peptides terminating at 42(43), species that foster Abeta deposition.

Aging, metabolism, and Alzheimer disease: review and hypotheses.

CE Finch — 2007-07-24T21:27:56-00:00

Exp Neurol, Vol. 143, No. 1. (January 1997), pp. 82-102.

Relationships are considered among aging, metabolism, and Alzheimer disease (AD). In particular, after 60 years, human populations show progressive age-related trends for increased blood glucose that are concurrent with the accelerating incidence of AD. The accumulation of glycated products in the AD brain, such as is also found in peripheral tissues during diabetes, suggests interactions of AD with age-related changes in metabolism. A review of 13 recent studies on AD and diabetes shows no consensus, although most studies indicate an apparent exclusion of AD and diabetes. We argue that longitudinal studies are needed to evaluate the possibility that an initial age-related hyperglycemic state is reversed by the cachexia and weight loss common to later stages of AD. A review of literature on chronic food restriction in rodents shows the slowing of some aspects of aging in the nervous system and generally supports interactions of peripheral metabolism with brain aging. Finally, we discuss aspects of intermediary metabolism that could ensue from oxidative damage to enzymes by glycation or oxidative stress which include excess production of ammonia from the inhibition of glutamine synthetase and the production of glyceraldehyde-3-phosphate, a glycating agent that could contribute to damage in addition to the hyperglycemic trends during aging.

Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein.

D Cai — 2007-07-24T21:03:15-00:00

J Biol Chem, Vol. 278, No. 5. (31 January 2003), pp. 3446-3454.

Presenilins (PS1/PS2) play a critical role in proteolysis of beta-amyloid precursor protein (beta APP) to generate beta-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of beta APP-containing vesicles from the trans-Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of beta APP. In contrast, release of vesicles containing beta APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced beta APP delivery to the cell surface. Moreover, diminution of surface beta APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of beta APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate beta APP processing.

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

R Sherrington — 2007-07-24T20:04:02-00:00

Nature, Vol. 375, No. 6534. (29 June 1995), pp. 754-760.

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.

Model-guided microarray implicates the retromer complex in Alzheimer's disease.

Scott A Small — 2005-12-01T09:43:06-00:00

Ann Neurol, Vol. 58, No. 6. (28 November 2005), pp. 909-919.

Although, in principle, gene expression profiling is well suited to isolate pathogenic molecules associated with Alzheimer's disease (AD), techniques such as microarray present unique analytic challenges when applied to disorders of the brain. Here, we addressed these challenges by first constructing a spatiotemporal model, predicting a priori how a molecule underlying AD should behave anatomically and over time. Then, guided by the model, we generated gene expression profiles of the entorhinal cortex and the dentate gyrus, harvested from the brains of AD cases and controls covering a broad age span. Among many expression differences, the retromer trafficking molecule VPS35 best conformed to the spatiotemporal model of AD. Western blotting confirmed the abnormality, establishing that VPS35 levels are reduced in brain regions selectively vulnerable to AD. VPS35 is the core molecule of the retromer trafficking complex and further analysis revealed that VPS26, another member of the complex, is also downregulated in AD. Cell culture studies, using small interfering RNAs or expression vectors, showed that VPS35 regulates Abeta peptide levels, establishing the relevance of the retromer complex to AD. Reviewing our findings in the context of recent studies suggests how downregulation of the retromer complex in AD can regulate local levels of Abeta peptide. Ann Neurol 2005;58:909-919.

The genetics of adult-onset neuropsychiatric disease: complexities and conundra?

JL Kennedy — 2007-07-24T19:13:02-00:00

Science, Vol. 302, No. 5646. (31 October 2003), pp. 822-826.

Genetic factors play a major role in the etiology of adult-onset neurodegenerative and neuropsychiatric disorders. Several highly penetrant genes have been cloned for rare, autosomal-dominant, early-onset forms of neurodegenerative diseases. These genes have provided important insights into the mechanisms of these diseases (often altering neuronal protein processing). However, the genes associated with inherited susceptibility to late-onset neurodegenerative diseases, schizophrenia, and bipolar disorder appear to have smaller effects and are likely to interact with each other (and with nongenetic factors) to modulate susceptibility and/or disease phenotype. Several strategies have recently been applied to address this complexity, leading to the identification of a number of candidate susceptibility loci/genes.

The genetic epidemiology of neurodegenerative disease.

L Bertram — 2007-07-24T19:06:58-00:00

J Clin Invest, Vol. 115, No. 6. (June 2005), pp. 1449-1457.

Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.

Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis.

SA Small — 2007-07-24T19:03:06-00:00

Neuron, Vol. 52, No. 1. (5 October 2006), pp. 15-31.

During the first 100 years of Alzheimer's disease research, this devastating and intractable disorder has been characterized at the clinical, histological, and molecular levels. Nevertheless, many key mechanistic questions remain unanswered. Here we will emphasize the importance of the cell biology of Alzheimer's disease, reviewing the relevant literature that has expanded our mechanistic understanding, with a particular focus on pathways regulating protein sorting. Accumulated evidence indicates that sorting pathways may be uniquely vulnerable to disease pathogenesis, and recent studies have begun to reveal disease-related defects in the regulation of protein sorting.

Imaging-guided microarray: isolating molecular profiles that dissociate Alzheimer's disease from normal aging.

AC Pereira — 2007-07-24T17:21:25-00:00

Ann N Y Acad Sci, Vol. 1097 (February 2007), pp. 225-238.

Although both Alzheimer's disease (AD) and normal aging contribute to age-related hippocampal dysfunction, they are likely governed by separate molecular mechanisms. In principle, gene expression profiling can offer molecular clues about underlying mechanisms, but in practice techniques like microarray present unique analytic challenges when applied to disorders of the brain. Imaging-guided microarray is an approach designed to address these analytic challenges. Here, we will first review findings applying variants of functional magnetic resonance imaging (fMRI) to AD and normal aging, establishing the spatiotemporal profiles that dissociate one from the other. Then, we will review preliminary findings applying imaging-guided microarray to AD and normal aging, in an attempt to isolate molecular profiles that dissociate the two main causes of age-related hippocampal dysfunction.

The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome

Kitt Petersen — 2007-07-19T16:49:05-00:00

PNAS (18 July 2007), 0705408104.

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 1, 2007.Contributed by Gerald I. Shulman, June 8, 2007 (sent for review May 25, 2007)We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approx60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approx20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome. 10.1073/pnas.0705408104

Mining gene expression profiles: expression signatures as cancer phenotypes

Joseph Nevins — 2007-07-18T23:16:35-00:00

Nature Reviews Genetics, Vol. 8, No. 8. (03 July 2007), pp. 601-609.

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes.

A McShea — 2007-07-18T19:04:28-00:00

Biochim Biophys Acta, Vol. 1772, No. 4. (April 2007), pp. 467-472.

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

BRCA1 may modulate neuronal cell cycle re-entry in Alzheimer disease.

TA Evans — 2007-07-18T19:03:46-00:00

Int J Med Sci, Vol. 4, No. 3. (2007), pp. 140-145.

In Alzheimer disease, neuronal degeneration and the presence of neurofibrillary tangles correlate with the severity of cognitive decline. Neurofibrillary tangles contain the antigenic profile of many cell cycle markers, reflecting a re-entry into the cell cycle by affected neurons. However, while such a cell cycle re-entry phenotype is an early and consistent feature of Alzheimer disease, the mechanisms responsible for neuronal cell cycle are unclear. In this regard, given that a dysregulated cell cycle is a characteristic of cancer, we speculated that alterations in oncogenic proteins may play a role in neurodegeneration. To this end, in this study, we examined brain tissue from cases of Alzheimer disease for the presence of BRCA1, a known regulator of cell cycle, and found intense and specific localization of BRCA1 to neurofibrillary tangles, a hallmark lesion of the disease. Analysis of clinically normal aged brain tissue revealed systematically less BRCA1, and surprisingly in many cases with apparent phosphorylated tau-positive neurofibrillary tangles, BRCA1 was absent, yet BRCA1 was present in all cases of Alzheimer disease. These findings not only further define the cell cycle reentry phenotype in Alzheimer disease but also indicate that the neurofibrillary tangles which define Alzheimer disease may have a different genesis from the neurofibrillary tangles of normal aging.

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

Dohoon Kim — 2007-06-21T19:03:13-00:00

The EMBO Journal, Vol. aop, No. current. (21 June 2007)

Detecting genetic variation in microarray expression data

Jennifer Greenhall — 2007-07-05T19:56:30-00:00

Genome Res. (3 July 2007), gr.6307307.

The use of high-density oligonucleotide arrays to measure the expression levels of thousands of genes in parallel has become commonplace. To take further advantage of the growing body of data, we developed a method, termed "GeSNP," to mine the detailed hybridization patterns in oligonucleotide array expression data for evidence of genetic variation. To demonstrate the performance of the algorithm, the hybridization patterns in data obtained previously from SAMP8/Ta, SAMP10/Ta, and SAMR1/Ta inbred mice and from humans and chimpanzees were analyzed. Genes with consistent strain-specific and species-specific hybridization pattern differences were identified, and [~]90% of the candidate genes were independently confirmed to harbor sequence differences. Importantly, the quality of gene expression data was also improved by masking the probes of regions with putative sequence differences between species and strains. To illustrate the application to human disease groups, data from an inflammatory bowel disease study were analyzed. GeSNP identified sequence differences in candidate genes previously discovered in independent association and linkage studies and uncovered many promising new candidates. This approach enables the opportunistic extraction of genetic variation information from new or pre-existing gene expression data obtained with high-density oligonucleotide arrays. 10.1101/gr.6307307

Effects of sex and age on regional prefrontal brain volume in two human cohorts

Cowell — 2007-01-17T21:27:17-00:00

European Journal of Neuroscience, Vol. 25, No. 1. (January 2007), pp. 307-318.

Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: Inverse relationships during postadolescent brain maturation.

ER Sowell — 2007-07-03T20:55:31-00:00

J Neurosci, Vol. 21, No. 22. (15 November 2001), pp. 8819-8829.

Recent in vivo structural imaging studies have shown spatial and temporal patterns of brain maturation between childhood, adolescence, and young adulthood that are generally consistent with postmortem studies of cellular maturational events such as increased myelination and synaptic pruning. In this study, we conducted detailed spatial and temporal analyses of growth and gray matter density at the cortical surface of the brain in a group of 35 normally developing children, adolescents, and young adults. To accomplish this, we used high-resolution magnetic resonance imaging and novel computational image analysis techniques. For the first time, in this report we have mapped the continued postadolescent brain growth that occurs primarily in the dorsal aspects of the frontal lobe bilaterally and in the posterior temporo-occipital junction bilaterally. Notably, maps of the spatial distribution of postadolescent cortical gray matter density reduction are highly consistent with maps of the spatial distribution of postadolescent brain growth, showing an inverse relationship between cortical gray matter density reduction and brain growth primarily in the superior frontal regions that control executive cognitive functioning. Inverse relationships are not as robust in the posterior temporo-occipital junction where gray matter density reduction is much less prominent despite late brain growth in these regions between adolescence and adulthood. Overall brain growth is not significant between childhood and adolescence, but close spatial relationships between gray matter density reduction and brain growth are observed in the dorsal parietal and frontal cortex. These results suggest that progressive cellular maturational events, such as increased myelination, may play as prominent a role during the postadolescent years as regressive events, such as synaptic pruning, in determining the ultimate density of mature frontal lobe cortical gray matter.

A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes.

P Baldi — 2005-06-30T17:14:46-00:00

Bioinformatics, Vol. 17, No. 6. (June 2001), pp. 509-519.

MOTIVATION: DNA microarrays are now capable of providing genome-wide patterns of gene expression across many different conditions. The first level of analysis of these patterns requires determining whether observed differences in expression are significant or not. Current methods are unsatisfactory due to the lack of a systematic framework that can accommodate noise, variability, and low replication often typical of microarray data. RESULTS: We develop a Bayesian probabilistic framework for microarray data analysis. At the simplest level, we model log-expression values by independent normal distributions, parameterized by corresponding means and variances with hierarchical prior distributions. We derive point estimates for both parameters and hyperparameters, and regularized expressions for the variance of each gene by combining the empirical variance with a local background variance associated with neighboring genes. An additional hyperparameter, inversely related to the number of empirical observations, determines the strength of the background variance. Simulations show that these point estimates, combined with a t -test, provide a systematic inference approach that compares favorably with simple t -test or fold methods, and partly compensate for the lack of replication.

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration

Jennifer Gass — 2006-10-02T08:35:19-00:00

Hum. Mol. Genet., Vol. 15, No. 20. (15 October 2006), pp. 2988-3001.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers. 10.1093/hmg/ddl241

Limma: linear models for microarray data.

GK Smyth — 2007-06-28T13:41:10-00:00

(2005), pp. 397-420.

Bioconductor: open software development for computational biology and bioinformatics.

RC Gentleman — 2005-04-21T13:38:17-00:00

Genome Biol, Vol. 5, No. 10. (2004)

The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

Molecular classification based on peripheral gene expression profiles in FTD and AD: A Pilot Study [abstract IN2-1.006].

G Coppola — 2007-06-28T03:57:58-00:00

Neurology

Successful Design and Conduct of Genome-Wide Association Studies

Christopher Amos — 2007-06-27T21:41:24-00:00

Hum. Mol. Genet. (27 June 2007), ddm161.

Genome wide association studies are becoming an increasingly effective tool for identifying genetic factors contributing to complex diseases. In this review, I discuss two sets of genome-wide association studies that identified novel genetic factors for age-related macular degeneration and genetic factors for type II diabetes. In reviewing these sets of studies, my goal is to identify factors that contributed to the success of these studies. Design related factors include the selection of traits that show strong familiality, the selection of clinically homogeneous populations, and selecting cases that have a family history. Ethnic stratification within the study sample can lead to biases and methods to control for stratification are briefly reviewed. Finally, the impact of SNP selection on the power of a study and procedures for improving power by inferring genotypes, by combining data across studies and by performing multistage analyses are discussed. The continuing success of genome-wide association studies depends upon careful selection of populations for study and on collaborative analytical approaches. 10.1093/hmg/ddm161

Frataxin is essential for extramitochondrial Fe-S cluster proteins in mammalian tissues

Alain Martelli — 2007-06-27T21:40:38-00:00

Hum. Mol. Genet. (27 June 2007), ddm163.

Friedreich ataxia, the most common recessive ataxia, is due to deficiency of the mitochondrial protein frataxin, an iron chaperone involved in the assembly of Fe-S clusters (ISC). In yeast, mitochondria play a central role for all Fe-S proteins, independently of their subcellular localization. In mammalian cells, this central role of mitochondria remains controversial as an independent cytosolic ISC assembly machinery has been suggested. In the present work, we show that three extramitochondrial Fe-S proteins (xanthine oxido-reductase, glutamine phosphoribosylpyrophosphate amidotransferase, and Nth1) are affected in frataxin-deleted mouse tissues. Furthermore, we show that frataxin is strictly localized to the mitochondria, excluding the presence of a cytosolic pool of frataxin in normal adult tissues. Together, these results demonstrate that in mammals, frataxin and mitochondria play a cardinal role in the maturation of extramitochondrial Fe-S proteins. Furthermore, we show that the Fe-S scaffold protein IscU progressively decreases in frataxin-deleted tissues, further contributing to the impairment of Fe-S proteins. These results thus provide new cellular pathways that may contribute to molecular mechanisms of the disease. 10.1093/hmg/ddm163

Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays

Andrea Malaspina — 2007-06-27T18:06:10-00:00

Journal of Neurochemistry, Vol. 77, No. 1. (2001), pp. 132-145.

In order to obtain insight into the aetiology and pathogenesis of amyotrophic lateral sclerosis (ALS), high-density gene discovery arrays (GDA human version 1.2) containing 18 400 non-redundant EST cDNAs pooled from different tissue libraries have been used to monitor gene expression in lumbar spinal cord from ALS cases compared with controls. Quantitative filter analysis revealed differential expression of cDNAs normalized to internal standards. These candidates have been further investigated and their expression in spinal cord characterized in a panel of ALS and control subjects. Significant differential expression was obtained for 14 genes, 13 being elevated (up to six-fold) and one decreased (by 80%) in ALS. Amongst those elevated in ALS were thioredoxin and glial fibrilary acid protein, which have already been shown to be up-regulated in ALS, thus supporting the reliability of this approach. The other differentially regulated transcripts confirmed in the expression studies represent potential candidates in ALS pathogenesis being involved in antioxidant systems, neuroinflammation, the regulation of motor neurone function, lipid metabolism, protease inhibition and protection against apoptosis. The use of the GDA system has greatly facilitated the screening and retrieval of sequence information and has generated useful information on the cascade of molecular events occurring in ALS and potentially may highlight new candidates playing a role in the aetiology and progression of this disease.

Adjusting batch effects in microarray expression data using empirical Bayes methods

Johnson — 2007-01-21T05:33:25-00:00

Biostatistics, Vol. 8, No. 1. (January 2007), pp. 118-127.

The complementary deoxyribonucleic acid sequence, tissue distribution, and cellular localization of the rat granulin precursor.

V Bhandari — 2007-06-27T17:06:14-00:00

Endocrinology, Vol. 133, No. 6. (December 1993), pp. 2682-2689.

Granulins (grns; also called epithelins) are cysteine-rich polypeptides with pleiotropic effects on epithelial cell growth in vitro. The grn/epi gene is widely expressed in epithelial cell lines, many of which respond to the gene product, raising the possibility of autocrine or paracrine regulation. In vitro the grn gene is expressed in cell types of diverse lineages, including epithelial cells, lymphoid and myeloid cells, and fibroblasts, but it is not known which cells express the gene in vivo. To understand the physiological role of the grn gene products it is necessary to know the context of grn gene expression in vivo. We have isolated the rat grn precursor complementary DNA and determined, by Northern blot analysis and in situ hybridization, the tissue distribution and cellular localization of grn gene expression. The complementary DNA predicts a 589-amino acid protein of M(r) 63,500 with seven and one-half grn repeats arranged in tandem and shows an overall identity of 75% with human progrn. The grn gene is expressed in a variety of tissues derived from all three embryonic germ layers but is most abundant in the spleen and several tissues of endocrine significance including the adrenal glands, epididymis, placenta, and ovary. Although widely expressed in tissues, gene expression is restricted to specific cell types. For example in the kidney, grn messenger RNA was detected in epithelial cells of the proximal and distal convoluted tubules and Bowman's capsule but not in medullary epithelia. In the spleen, grn messenger RNA expression was localized in lymphocytes, whereas hybridization signals were detected over scattered hepatocytes in the liver. Thus, although the grn gene is widely expressed in tissues and cell lines of many lineages in vitro, its expression in situ is restricted to hematopoietic and some epithelial cells. The restricted cell distribution suggests that the expression of the grn gene is more closely regulated in vivo than in cell cultures. Its localization to epithelial cells in situ supports an autocrine or paracrine role for these factors.

Progranulin in frontotemporal lobar degeneration and neuroinflammation

Zeshan Ahmed — 2007-02-12T06:00:53-00:00

Journal of Neuroinflammation, Vol. 4 (11 February 2007), 7.

Microarrays and the microscope: balancing throughput with resolution

Coppola — 2006-08-25T23:36:58-00:00

The Journal of Physiology, Vol. 575, No. 2. (September 2006), pp. 353-359.

Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect

Leslie Nangle — 2007-06-27T15:18:34-00:00

PNAS (26 June 2007), 0705055104.

Contributed by Paul Schimmel, May 29, 2007 (sent for review May 21, 2007)Charcot-Marie-Tooth (CMT) diseases are the most common heritable peripheral neuropathy. At least 10 different mutant alleles of GARS (the gene for glycyl-tRNA synthetase) have been reported to cause a dominant axonal form of CMT (type 2D). A unifying connection between these mutations and CMT has been unclear. Here, mapping mutations onto the recently determined crystal structure of human GlyRS showed them within a band encompassing both sides of the dimer interface, with two CMT-causing mutations being at sites that are complementary partners of a "kissing" contact across the dimer interface. The CMT phenotype is shown here to not correlate with aminoacylation activity. However, most mutations affect dimer formation (to enhance or weaken). Seven CMT-causing variants and the wild-type protein were expressed in transfected neuroblastoma cells that sprout primitive neurites. Wild-type GlyRS distributed into the nascent neurites and was associated with normal neurite sprouting. In contrast, all mutant proteins were distribution-defective. Thus, CMT-causing mutations of GlyRS share a common defect in localization. This defect may be connected in some way to a change in the surfaces at the dimer interface. 10.1073/pnas.0705055104

Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich ataxia patients and carriers.

L Pianese — 2007-06-27T14:29:25-00:00

J Neurol Neurosurg Psychiatry, Vol. 75, No. 7. (July 2004), pp. 1061-1063.

The most common causative mutation of Friedreich ataxia (FRDA) is the unstable hyperexpansion of an intronic GAA triplet repeat that impairs frataxin transcription. Using real time quantitative PCR, we showed that FRDA patients had residual levels of frataxin mRNA ranging between 13% and 30% and that FRDA carriers had about 40% of that of controls. Asymptomatic carriers also showed reduced frataxin mRNA levels. We found an inverse correlation between the number of GAA repeats and frataxin mRNA levels. Real-time quantitative PCR may represent an alternative assay for FRDA molecular diagnosis.