Grant: Operating Grant - Priority Announcement: Neuromuscular Research

Abnormal accumulations of neurofilaments are a pathological hallmark of many human neurodegenerative disorders including peripheral neuropathies and amyotrophic lateral sclerosis (ALS). However, the exact molecular mechanisms underlying the toxicity of neurofilament disorganization are unknown. We will address this question by the characterization of new transgenic mouse models with neurofilament abnormalities generated in our laboratory. First, propose to elucidate the pathogenic mechanisms of Charcot-Marie-Tooth type 2E (CMT2E) neuropathy and to rescue it by gene therapy using a mouse model with conditional expression of NF-LP22S mutant that recapitulates key features of CMT2E disease. Second, we will investigate the role of peripherin in transgenic mice models of ALS overexpressing human genomic fragments encoding TDP43 or ALS-linked TDP43 mutants. Our general hypothesis is that IF abnormalities can contribute to CMT2E neuropathy and to ALS disease by causing axonal transport defects.