Title | REST and stress resistance in ageing and Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Lu, T, Aron, L, Zullo, J, Pan, Y, Kim, H, Chen, Y, Yang, T-H, Kim, H-M, Drake, D, X Liu, S, Bennett, DA, Colaiácovo, MP, Yankner, BA |
Journal | Nature |
Volume | 507 |
Issue | 7493 |
Pagination | 448-54 |
Date Published | 2014 Mar 27 |
ISSN | 1476-4687 |
Keywords | Aged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Autophagy, Brain, Caenorhabditis elegans Proteins, Cell Death, Cell Nucleus, Chromatin Immunoprecipitation, Cognition, DNA-Binding Proteins, Down-Regulation, Frontotemporal Dementia, Gene Expression Regulation, Humans, Lewy Body Disease, Longevity, Mice, Mild Cognitive Impairment, Neurons, Neuroprotective Agents, Oxidative Stress, Phagosomes, Repressor Proteins, Transcription Factors, Up-Regulation, Wnt Signaling Pathway, Young Adult |
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. |
DOI | 10.1038/nature13163 |
Alternate Journal | Nature |
PubMed ID | 24670762 |
PubMed Central ID | PMC4110979 |
Grant List | DP1 AG044161 / AG / NIA NIH HHS / United States DP1 OD006849 / OD / NIH HHS / United States DP1OD006849 / OD / NIH HHS / United States P01 AG027916 / AG / NIA NIH HHS / United States P01AG27916 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States P30AG10161 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States R01 AG026651 / AG / NIA NIH HHS / United States R01 GM105853 / GM / NIGMS NIH HHS / United States R01AG15819 / AG / NIA NIH HHS / United States R01AG17917 / AG / NIA NIH HHS / United States R01AG26651 / AG / NIA NIH HHS / United States R01GM072551 / GM / NIGMS NIH HHS / United States T32 AG000222 / AG / NIA NIH HHS / United States |
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