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Nature. 2014 Mar 27;507(7493):448-54. doi: 10.1038/nature13163. Epub 2014 Mar 19.

REST and stress resistance in ageing and Alzheimer's disease.

Author information

1
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Department of Biostatistics and Computational Biology, Dana-Faber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois 60612, USA.

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.

PMID:
24670762
PMCID:
PMC4110979
DOI:
10.1038/nature13163
[Indexed for MEDLINE]
Free PMC Article

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