The role of inclusions in ALS pathogenesis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily afflicts motor neurons, leading to paralysis and death within 3 to 5 years after diagnosis. Genetic studies have uncovered multiple genetic defects causing familial forms of ALS and mutations occurring in proteins with a variety of functions, including RNA metabolism (TDP43, FUS) and oxygen free radical homeostasis (SOD1). A commonality among all ALS forms is the presence of intracellular inclusions that primarily consist of insoluble protein aggregates. These inclusions indicate that protein aggregation is a central pathogenic event shared by multiple ALS forms. The research of the present thesis focuses on the role of protein aggregation and inclusion formation in two types of ALS: 1) ALS caused by mutations in the superoxide dismutase 1 (SOD1) gene (ALS1); and 2) ALS caused by mutations in the vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) gene (ALS8)