RRC ID 30650
Author Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA.
Title REST and stress resistance in ageing and Alzheimer's disease.
Journal Nature
Abstract Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.
Volume 507(7493)
Pages 448-54
Published 2014-3-27
DOI 10.1038/nature13163
PII nature13163
PMID 24670762
PMC PMC4110979
MeSH Aged Aged, 80 and over Aging / genetics Aging / metabolism* Aging / pathology Alzheimer Disease / genetics Alzheimer Disease / metabolism* Alzheimer Disease / pathology Amyloid beta-Peptides / antagonists & inhibitors Amyloid beta-Peptides / toxicity Animals Autophagy Brain / cytology Brain / metabolism Brain / pathology Caenorhabditis elegans Proteins / metabolism Cell Death / genetics Cell Nucleus / metabolism Chromatin Immunoprecipitation Cognition Cognitive Dysfunction / metabolism DNA-Binding Proteins / metabolism Down-Regulation Frontotemporal Dementia / metabolism Frontotemporal Dementia / pathology Gene Expression Regulation Humans Lewy Body Disease / metabolism Lewy Body Disease / pathology Longevity Mice Neurons / cytology Neurons / metabolism Neurons / pathology Neuroprotective Agents / metabolism Oxidative Stress* / genetics Oxidative Stress* / physiology Phagosomes Repressor Proteins / deficiency Repressor Proteins / genetics Repressor Proteins / metabolism* Transcription Factors / metabolism Up-Regulation Wnt Signaling Pathway Young Adult
IF 41.577
Times Cited 157
WOS Category NEUROSCIENCES
Resource
C.elegans tm465 tm776