Misfolded SOD1 in ALS pathogenesis
The first genetic cause of ALS to be discovered (in 1993) encoded a mutation in protein called superoxide dismutase 1 (SOD1). Decades later, it is largely agreed upon that the abnormal shape (called misfolding) of SOD1 mutants is at the root of toxicity in some forms of ALS. Traditionally, misfolded SOD1 has been considered a single abnormal protein, but recent evidence suggests this might not be the case. Dr. Christine Vande Velde of Université de Montréal will examine the possibility that there are actually multiple different misfolded forms of SOD1 that might be toxic in unique ways and through involvement with different biological mechanisms. In particular, Dr. Vande Velde is interested in understanding which processes in cells are most important for conferring disease and to further study why several previous attempts to treat ALS model mice by neutralizing SOD1 has only shown mild benefit. If indeed there are multiple forms of misfolded SOD1 as Dr. Vande Velde hypothesizes, then these attempts targeting only one form might explain these results. In this Discovery Grant, Dr. Vande Velde will specifically focus on SOD1 forms that interact with the structures in cells that make energy called mitochondria (the cell’s “batteries”). Her hypothesis suggests that a specific form of SOD1, stuck to mitochondria before symptoms begin in ALS rats, may start a process that triggers the accumulation of another form of misfolded SOD1 leading to dysfunction. The potential of this work is not only to better understand SOD1`s role in the disease, but it will also affect ongoing and future therapeutic strategies aimed at removing or neutralizing misfolded forms of the protein, most importantly, the potential to improve immunotherapies that currently target only specific types of misfolded SOD1.
Christine Vande Velde , Université de Montréal
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ALS Society of Canada