HOT

TOPICS

REST as a New Therapeutic Target for Neurodegenerative Disorders Lu T, Aron L, Zullo J, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2014;507:448-454.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and currently has no cure. Its onset and progression are influenced by multiple factors. The preservation of cognitive function with ageing has emerged as one of the major medical challenges of the 21st century. A key question to be elucidated is why some individuals age with relatively preserved cognitive function whereas others decline and develop AD. Neuronal cell death is both a normal developmental process and a catastrophic outcome of nervous system trauma or degenerative disorders. Therefore, genes involved during embryonic development could be important as factors involved in neuronal cell death. Lu et al.1 report that the repressor element 1–silencing transcription factor (REST) is induced in the ageing human brain and regulates a network of genes that mediate cell death, stress resistance, and AD pathological conditions.1 REST is a repressor of neuronal genes during embryonic development that is downregulated once terminal neuronal differentiation has occurred. In contrast, transcriptional profiling has also demonstrated significant changes in the expression of neuronal genes such in the prefrontal cortex in the ageing human brain.2,3 Analysis of this data set, using the Ingenuity Systems IPA platform, indicates that the transcription factor most strongly predicted to be activated in the ageing brain is REST (P 5 9 3 10210). This gene network becomes dysregulated in the early stages of AD when REST is lost from the nucleus. Conditional REST knockout mice and Caenorhabditis elegans models suggest that REST protects neurons from age-related toxic insults. In ageing humans, elevated REST levels are associated with preservation of cognitive function and increased longevity, even in the presence of AD pathological conditions. Hence, REST appears to regulate a neuroprotective stress response that may be central to preservation of cognitive function. Interestingly, loss of REST from the nucleus was often accompanied by localization to punctate cytoplasmic structures that were labeled with autophagosome markers. Indeed, activated autophagy by serum deprivation in the

culture system resulted in significantly reduced nuclear REST, which was reversed by inhibition of autophagy. Induction of autophagy in neurodegenerative disorders has been involved in pathogenic misfolded proteins such as Ab, phosphorylated tau, TAR DNA-binding protein 43 kDa (TDP-43), and a-synuclein. Such misfolded proteins localized with REST and microtubule-associated protein 1 light chain 3 (LC3)-positive autophagosomes. In each of these disorders, REST was lost from the nucleus and appeared in autophagosomes, along with proteins such as Ab, phosphorylated tau, TDP-43, and a-synuclein. This may represent a common pathway that links altered proteostasis to aberrant gene expression. Finally, older individuals who harbor substantial AD pathological conditions do not appear to progress to dementia when neuronal REST levels are high. This suggests the possibility that structural pathological conditions such as Ab and neurofibrillary tangles may not be sufficient in themselves to cause dementia, and that failure of the brain’s stress response system also may be necessary. Strategies to elevate nuclear REST levels may represent a new therapeutic approach in the management of not only AD but also Parkinson’s disease and amyotrophic lateral sclerosis. Nobutaka Hattori, MD, PhD Department of Neurology, JUntendo University, Tokyo, Japan

References 1.

Lu T, Aron L, Zullo J, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature 2014;507:448-454.

2.

Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883-891.

3.

Loerch PM, Lu T, Dakin KA, et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE 2008;3:e3329.

-----------------------------------------------------------Published online 15 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25910

Movement Disorders, Vol. 29, No. 7, 2014

869

REST as a new therapeutic target for neurodegenerative disorders.

REST as a new therapeutic target for neurodegenerative disorders. - PDF Download Free
48KB Sizes 0 Downloads 5 Views