Publication Date:
2014-03-29
Description:
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 beta-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 beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110979/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Tao -- Aron, Liviu -- Zullo, Joseph -- Pan, Ying -- Kim, Haeyoung -- Chen, Yiwen -- Yang, Tun-Hsiang -- Kim, Hyun-Min -- Drake, Derek -- Liu, X Shirley -- Bennett, David A -- Colaiacovo, Monica P -- Yankner, Bruce A -- DP1 AG044161/AG/NIA NIH HHS/ -- DP1 OD006849/OD/NIH HHS/ -- DP1OD006849/OD/NIH HHS/ -- P01 AG027916/AG/NIA NIH HHS/ -- P01AG27916/AG/NIA NIH HHS/ -- P30 AG010161/AG/NIA NIH HHS/ -- P30AG10161/AG/NIA NIH HHS/ -- R01 AG015819/AG/NIA NIH HHS/ -- R01 AG017917/AG/NIA NIH HHS/ -- R01 AG026651/AG/NIA NIH HHS/ -- R01 GM105853/GM/NIGMS NIH HHS/ -- R01AG15819/AG/NIA NIH HHS/ -- R01AG17917/AG/NIA NIH HHS/ -- R01AG26651/AG/NIA NIH HHS/ -- R01GM072551/GM/NIGMS NIH HHS/ -- T32 AG000222/AG/NIA NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):448-54. doi: 10.1038/nature13163. Epub 2014 Mar 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Biostatistics and Computational Biology, Dana-Faber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois 60612, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670762" target="_blank"〉PubMed〈/a〉
Keywords:
Aged
;
Aged, 80 and over
;
Aging/genetics/*metabolism/pathology
;
Alzheimer Disease/genetics/*metabolism/pathology
;
Amyloid beta-Peptides/antagonists & inhibitors/toxicity
;
Animals
;
Autophagy
;
Brain/cytology/metabolism/pathology
;
Caenorhabditis elegans Proteins/metabolism
;
Cell Death/genetics
;
Cell Nucleus/metabolism
;
Chromatin Immunoprecipitation
;
Cognition
;
DNA-Binding Proteins/metabolism
;
Down-Regulation
;
Frontotemporal Dementia/metabolism/pathology
;
Gene Expression Regulation
;
Humans
;
Lewy Body Disease/metabolism/pathology
;
Longevity
;
Mice
;
Mild Cognitive Impairment/metabolism
;
Neurons/cytology/metabolism/pathology
;
Neuroprotective Agents/metabolism
;
*Oxidative Stress/genetics/physiology
;
Phagosomes
;
Repressor Proteins/deficiency/genetics/*metabolism
;
Transcription Factors/metabolism
;
Up-Regulation
;
Wnt Signaling Pathway
;
Young Adult
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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