Grant: Operating Grant - Priority Announcement: Neuromuscular Research

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the loss of motor neurons in the brain and spinal cord, progressing from a mild muscle weakness to complete paralysis and eventual death, usually from respiratory failure, within 2-5 years from diagnosis. The incidence is about 2 per 100,000 with 2000-3000 Canadians suffering from the disease at any one time. There is no cure, nor effective treatment. Peripherin is a protein that is found associated with many of the pathological abnormalities found in the diseased motor neurons of patients with ALS. Overexpression of peripherin in transgenic mice leads to the formation of pathological abnormalities similar to those seen in ALS, that precedes a massive age related motor neuron degeneration, closely modeling the disease. This evidence suggests that peripherin may be an important factor contributing to motor neuron degeneration in ALS. This is supported by the finding of mutations in the peripherin gene in a few ALS cases. We have shown that many different peripherin species, or isoforms, can be generated by a process called alternative splicing, and that changes in peripherin isoform expression causes peripherin aggregate formation, and in some cases, neuronal death. We have shown that there is deregulation of alternative splicing of peripherin in ALS generating disease specific isoforms that may have utility as diagnostic markers. This proposal is aimed at further characterizing peripherin abnormalities in ALS as a means to understanding the underlying pathogenic process, which will aid in the development of effective therapeutics and eventual cure.