Year
2022
Degree Name
Doctor of Philosophy
Department
School of Medical, Indigenous and Health Sciences
Abstract
Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection that forms a complex with the corepressor of REST1 (CoREST1), CoREST2 and CoREST3 (encoded by RCOR1, RCOR2 and RCOR3, respectively). Emerging evidence suggests the CoREST family have the ability to target unique genes, in a RESTindependent manner, in various neural and glial cell types at different stages of development. There is limited knowledge on expression and function of CoREST3 in neurodevelopment and neurodegeneration, particularly in humans. This study used 2D and 3D human pluripotent stem cell (hPSC) models to interrogate RCOR3 gene expression levels in human neurons using RT-qPCR. RCOR3 expression was shown to significantly increase in glutamatergic cortical and GABAergic ventral forebrain neurons, mature functional NGN2 induced neurons and a trend for an increase in 3D cerebral organoids. CoREST3 was shown to have an age-related and region-specific expression pattern in the aging rat brain, with expression in the prefrontal cortex increasing in adult rats (postnatal day 96) and in the caudate putamen in aged rats (~14 months) via western blotting. CoREST3 expression was analysed in an AD post-mortem tissue of four brain regions that are affected with varying severity via western blot analysis. The brain regions, in order of decreasing neuronal loss, were the superior temporal gyrus (STG), inferior temporal gyrus (ITG), precuneus (PRE) and primary visual cortex (PVC) (n = 23 AD, n = 18 matched controls). Neuronal counts showed a significant reduction only in the STG. The full-length CoREST3, isoform A, was significantly decreased by ~ 30 % in AD compared to age- and sex-matched controls. RCOR3 shRNA knockdown in cortical neurons derived from hPSCs resulted in a trend for an increase in the cortical neural progenitor marker, PAX6, and neuronal markers TUBB3 (encodes ß-III-tubulin) and MAP2, in addition to a trend for increased neurite length. A significant increase in HDAC2 expression was also observed in cortical neurons following CoREST3 gene knockdown. In summary, our findings are the first to show an increase of RCOR3 expression with human embryonic neural differentiation, CoREST3 to be expressed in healthy adult brain and expression disrupted in AD. In addition to a potential neuroprotective role for CoREST3 in the regulation HDAC2 expression, which may be diminished in AD. Better understanding the regulatory networks of the brain will deepen our understanding of the biological basis of neurodegeneration.
Recommended Citation
Maksour, Simon, Expression and role of CoREST3 in neurodevelopment and neurodegeneration, Doctor of Philosophy thesis, School of Medical, Indigenous and Health Sciences, University of Wollongong, 2022. https://ro.uow.edu.au/theses1/1589
FoR codes (2020)
310104 Cell neurochemistry, 310504 Epigenetics (incl. genome methylation and epigenomics), 320903 Central nervous system, 320905 Neurology and neuromuscular diseases
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.