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Autophagy and neurodegeneration

Published on Jan 2, 2015in Journal of Clinical Investigation12.282
· DOI :10.1172/JCI73944
Rebecca A. Frake2
Estimated H-index: 2
,
Thomas Ricketts9
Estimated H-index: 9
+ 1 AuthorsDavid C. Rubinsztein115
Estimated H-index: 115
Sources
Abstract
Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.
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  • Citations (147)
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References151
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Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.
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Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical n...
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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown...
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