Mutual regulation between RE1 Silencing Transcription Factor (REST) and Mitochondria in Neurodegenerative Disease
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The molecular basis of the earliest neuronal changes that lead to Alzheimer’s disease (AD) is unclear. Ageing represents the main risk factor for the development of AD. Albeit being distinct phenomena, brain ageing and AD share common features of reduced brain bioenergetics and oxidative stress. Oxidative stress is observed at early stages of AD and have been linked to mitochondrial function. As the brain ages, oxidative damage accumulates, leading to a vicious cycle of mitochondrial dysfunction and an increasing burden of oxidative stress, a concept summarized in the mitochondrial theory of ageing. The transcriptional repressor REST/NRSF is a master regulator of the global stress response system in the brain and can be induced by a variety of stress-related factors. It acts as a neuroprotective modulator by repressing pro-cell death and inflammation-related genes, by inducing neuroprotective genes, and by reducing the expression of genes involved in the pathology of Alzheimer’s disease (AD). Thus, the initial aim of this project was to elucidate the role of the transcription factor REST/NRSF in regulating the oxidative stress response in the brain and whether dysfunction of REST in AD contributes to the transition from normal aging to cognitive decline. However, when analyzing neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs), I observed accelerated neural differentiation and reduced progenitor cell renewal. Altered differentiation was accompanied by major gene regulatory differences. Importantly, impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 exhibited reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to Alzheimer’s disease.
Publications
- (2019). REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease. Cell Rep. 26, 1112-1127.e9
Meyer, K., Feldman, H.M., Lu, T., Drake, D., Lim, E.T., Ling, K.-H., Bishop, N.A., Pan, Y., Seo, J., Lin, Y.-T., et al.
(See online at https://doi.org/10.1016/j.celrep.2019.01.023)
