Étude et caractérisation du rôle de protéines TDP-43 mutantes dans la pathogénèse de la sclérose latérale amyotrophique (SLA)

Authors: Swarup, Vivek
Advisor: Julien, Jean-Pierre
Abstract: Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by degeneration of lower and upper motor neurons. Transactive response DNA-binding protein 43 (TDP-43) ubiquitinated inclusions are a hallmark of ALS. In order to understand the pathogenic mechanism caused by TDP-43, we generated transgenic mice with genomic fragments encoding human TDP-43 wild-type or FALS-linked mutants TDP-43G348C and TDP-43A315T. These novel TDP-43 transgenic mice develop many age-related pathological and biochemical changes reminiscent of human ALS including ubiquitinated TDP-43 positive inclusions, intermediate filament abnormalities, axonopathy and neuroinflammation. In order to understand the role of TDP-43 in axon regeneration, we used pre-symptomatic 3-months old mice and performed sciatic nerve crush on them. After axonal crush, TDP-43 transgenic mice were noticeably paralyzed at the injured limb, have altered TDP-43 redistribution and the distal axons regenerated slowly as compared to non-transgenic mice. Moreover, we found that TDP-43 interacts with and colocalizes with p65, a NF-κΒ subunit, in glial and neuronal cells from TDP-43 transgenic mice and also from ALS patients. We report that TDP-43 and NF-κΒ p65 mRNA and protein expression is higher in spinal cords of ALS patients than healthy individuals. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κΒ activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κΒ activation, and that NF-κΒ may constitute a therapeutic target for the disease.
Document Type: Thèse de doctorat
Issue Date: 2012
Open Access Date: 18 April 2018
Permalink: http://hdl.handle.net/20.500.11794/23287
Grantor: Université Laval
Collection:Thèses et mémoires

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