Protein Aggregation in Amyotrophic Lateral Sclerosis

The main pathological hallmark of amyotrophic lateral sclerosis (ALS) is the deposition of key proteins into insoluble intracellular inclusions in motor neurons. That protein aggregation is the major pathological hallmark of ALS is a strong indication that protein misfolding plays a key role in ALS pathogenesis. This chapter explores the cellular mechanisms involved in protein misfolding and aggregation, as well as the neural pathology associated with protein deposition as they relate to ALS. We discuss current ideas surrounding why specific proteins that are susceptible to misfolding are causative for ALS and discuss the evidence linking dysfunction in the proteostasis system with pathological consequences. Finally, we explore the role of misfolded protein in the prion‐like spread of protein misfolding and aggregation in ALS. The interconnectivity of aggregated proteins between neurodegenerative diseases implies similar converging pathobiological mechanisms, and elucidating these mechanisms may assist in the design of more effective therapies.