Propagation and Replication of Misfolded SOD1: Implications for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motor neuron disease, with 50 % of patients dying within 1.5 years of symptoms onset. The clinical manifestations are heterogeneous in ALS, as the region of onset of muscle weakness varies between individuals. Regardless of the site of onset, the symptoms of ALS begin in one discrete body region in 98 % of the cases. Subsequently, symptoms inevitably progress to regions contiguous to the site of onset where they appear with decreasing severity. These unique clinical features suggest that neurodegeneration in ALS is an orderly and propagating process. At the molecular level, it is now well recognized that protein misfolding plays a central role in both familial and sporadic ALS. Recently, it was found that mutant SOD1, the major component of the protein deposits in familial forms of ALS, propagates misfolding from cell to cell and replicates its misfolding conformation indefinitely, just like prions do. This phenomenon could provide the molecular basis of the focality and spreading of muscle weakness in ALS, as well as the cell autonomous and non-cell autonomous processes in ALS.