Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are two related neurodegenerative diseases which share overlapping clinical, pathologic and genetic features. The ALS/FTD spectrum of diseases is uniformly fatal, and there is neither treatment nor cure. The endogenous mechanisms which exacerbate or mitigate disease progression in these diseases are not clearly understood. However, a mutation within the C9orf72 gene has been discovered as the most common genetic cause of ALS/FTD. The mutation consists of a hexanucleotide repeat expansion which has been proposed to lead to the accumulation of toxic RNA and protein species. C9orf72 mutations are also associated with C9orf72 promoter hypermethylation in a subset of mutation carriers. Promoter hypermethylation appears to protect against many of the molecular aberrations associated with the C9orf72 mutation including DNA repeat instability, toxic RNA accumulation, dipeptide repeat protein accumulation and cellular vulnerability to stress. C9orf72 methylation also predicts prolonged disease duration, maintenance of grey matter, and preservation of memory function in FTD patients with the C9orf72 mutation. Based on these findings, the hypothesis of this proposal is that epigenetic editing of mutant C9orf72 can modulate disease pathogenesis. To test this hypothesis, I have developed a novel method of introducing or removing CpG methylation within the endogenous genome, and propose three specific aims to (1) determine the molecular mechanisms and specificity of targeted epigenetic editing, (2) introduce C9orf72 hypermethylation in patient-derived iPS cells as a proof-of-concept study to show that epigenetic targeting can be therapeutic, and (3) develop improved models of disease by demethylating the C9orf72 promoter in iPS cells with large C9orf72 repeat expansions. These studies will bring to reality the possibility of epigenetic editing as a means of modulating neurodegenerative disease phenotypes, and will highlight the utility of a novel epigenetic editing technique that is broadly applicable across many disciplines.
A mutation in the C9orf72 gene is the most common heritable cause of amyotrophic lateral sclerosis and frontotemporal degeneration, and epigenetic silencing of this mutation appears to be protective. This project will study a novel method of editing the epigenetic status of C9orf72 in order to protect cells from the deleterious effects of the mutation.
|Porta, Sílvia; Xu, Yan; Restrepo, Clark R et al. (2018) Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun 9:4220|
|Lee, Edward B (2018) Integrated neurodegenerative disease autopsy diagnosis. Acta Neuropathol 135:643-646|
|McGurk, L; Mojsilovic-Petrovic, J; Van Deerlin, V M et al. (2018) Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol Commun 6:84|
|Bonini, Nancy M; Lee, Edward B; Wasco, Wilma et al. (2017) Editorial overview: Molecular & genetic basis of disease. Curr Opin Genet Dev 44:iv-vi|
|Paolicelli, Rosa C; Jawaid, Ali; Henstridge, Christopher M et al. (2017) TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron 95:297-308.e6|
|Yousef, Ahmed; Robinson, John L; Irwin, David J et al. (2017) Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration. Acta Neuropathol Commun 5:68|
|Liu, Elaine Y; Cali, Christopher P; Lee, Edward B (2017) RNA metabolism in neurodegenerative disease. Dis Model Mech 10:509-518|
|Lee, Edward B; Porta, Sílvia; Michael Baer, G et al. (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65-78|