REST and Stress Resistance in Aging and Alzheimer’s Disease

By Tao Lu, Liviu Aron, Joseph M. Zullo, Ying Pan, Haeyoung Kim, Yiwen Chen, Tun-Hsiang Yang, Hyun-Min Kim, Derek Drake, Xiaole Liu and 3 more. Nature, 2014

755 citations recorded by the source corpus.

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.

Subfields: Aging, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8ea6aeeca8e026972033aa4159cb27f01d83782a

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Citations in the corpus

The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases,, (2015, background): “Currently, the REST increases that occur in Alzheimer’s disease have been reported to be neuroprotective (Lu et al., 2014), while those in Huntington’s disease and epilepsy have been reported to contribute to the pathogenetic process ( Zuccato et al.”
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 (2015, background): “We also examined GATA4 abundance in the human brain (59).”
Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “during embryonic development and has been shown to be protective in Alzheimer’s disease (Lu et al., 2014).”
Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects (2015, positive): “Similarly, the anti-neurogenic repressor element 1-silencing transcription factor (REST) is an important neuroprotective factor in the old brain that, when lost from the nucleus, might permit neurodegeneration (Lu et al., 2014).”
DNA methylation aging clocks: challenges and recommendations (2019, background): “Changes with aging have been observed in both the binding sites of the transcriptional repressor REST [83] and insulator CTCF [84].”
Immunosenescence: molecular mechanisms and diseases (2023, background): “elegans demonstrated the neuroprotective effect of REST in reducing sensitivity to oxidative stress.(184,185) However, published evidence on whether causal links exist between immunosenescence and neurodegeneration is still limited.”