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Supported by the generosity of the Killam Trusts, The Neuro's Killam Seminar Series invites outstanding guest speakers whose research is of interest to the scientific community at The Neuro and 51³Ô¹ÏÍø.

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±á´Ç²õ³Ù:ÌýGary Armstrong

Maxime W. Rousseaux, Ph.D.

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Abstract: TDP-43 mislocalization and aggregation are defining features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Building on our previous work identifying stress-dependent SUMOylation of TDP-43 at lysine 408 (K408), we examined whether loss of this modification drives neurodegeneration and how additional genetic or environmental stressors shape disease-relevant outcomes. Using Tdp-43^K408R knock-in mice, which lack this SUMOylation site, we assessed age-related pathology through behavioural, histological, and neuromuscular junction analyses, and further challenged animals with ALS/FTD-linked insults including a C9ORF72 repeat expansion and traumatic brain injury. Complementary studies employed human iPSC-derived motor neurons engineered with the K408R mutation. Aging Tdp-43^K408R mice developed spinal cord TDP-43 mislocalization, neuromuscular denervation, and mild cognitive impairment by 18 months, though phenotypes were modest—likely reflecting limited stress exposure under standard housing conditions. Nonetheless, combining TDP-43 SUMOylation deficiency with C9ORF72 expansion or traumatic injury exacerbated select behavioural and histopathological abnormalities. In parallel, the K408R mutation in human motor neurons altered TDP-43 SUMOylation and is being used to probe human-specific mechanisms. Together, these findings indicate that stress-dependent SUMOylation of TDP-43 is neuroprotective and that loss of this modification heightens vulnerability to genetic and environmental challenges, underscoring posttranslational regulation of TDP-43 as a potential therapeutic avenue in ALS and FTD.

Bio: Dr. Rousseaux is an Associate Professor and Canada Research Chair at uOttawa where his lab looks at how protein mislocalization drives neurodegeneration. His research group leverages high throughput screens and mouse genetics to examine the interplay between genes and environment in the context of disease. Dr. Rousseaux is recipient of funding from federal (CIHR, NSERC) and non-profit (ALS Canada, ASAP) funding sources and is a Fahn Scholar of the Parkinson’s Foundation and Brain Canada Future Leader.