Staff Scientist National Institute of Neurological Disorders and Stroke Bethesda, Maryland, United States
Abstract: The C9orf72 repeat expansion is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. A hallmark of these diseases is the cytoplasmic aggregation of TDP-43 in neurons but the underlying mechanisms by which the two are linked is poorly understood. Recent studies have shown that human endogenous retrovirus HERV-K reactivation in ALS and FTD. In vitro and in vivo studies show that expression of HERV-K is toxic to motor neurons. Hence we determined if HERV-K played a role in C9orf72 repeat expansion mediated pathogenesis in motor neurons. We generated iPSCs from peripheral blood hematopoietic progenitor cells of ALS patients with C9orf72 repeat expansions and controls and further differentiated them into motor neurons. We found HERV-K env expression in the motor neurons of the ALS patients using RT-PCR and increased total and phosphorylated TDP-43 production using Western-blot assay. Treatment with antisense oligonucleotides (ASO) targeting C9orf72 mutation decreased the HERV-K env activation in the C9orf72 motor neurons (P < 0.05). Further, treatment with ASOs targeting C9orf72 mutation or HERV-K env attenuated phosphorylated TDP-43 production in C9orf72 motor neurons (P < 0.05). The results indicate that C9of72 repeat expansion causes at least partially HERV-K activation and the subsequent TDP-43 neuropathology in motor neurons which can be attenuated using ASOs. The C9orf72 ALS-derived motor neurons reproduce TDP-43 neuropathology in ALS and therapeutic strategies targeting HERV-K could be useful in this patient population.
Funding Source: This project is supported by NINDS intramural fund.
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