From molecule to molecule and cell to cell: Prion-like mechanisms in amyotrophic lateral sclerosis

• We summarize the current evidence for prion-like activity in ALS.
• Mutant SOD1 can impart its misfold onto wild-type SOD1 inside living cells.
• Wild-type SOD1 misfolding can propagate from cell to cell.
• TDP-43 aggregation is self-propagating in cells.
• Intercellular transmission of misfolded ALS proteins can occur via exosomes.

Prions, self-proliferating infectious agents consisting of misfolded protein, are most often associated with aggressive neurodegenerative diseases in animals and humans. Akin to the contiguous spread of a living pathogen, the prion paradigm provides a mechanism by which a mutant or wild-type misfolded protein can dominate pathogenesis through self-propagating protein misfolding, and subsequently spread from region to region through the central nervous system. The prion diseases, along with more common neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and the tauopathies belong to a larger group of protein misfolding disorders termed proteinopathies that feature aberrant misfolding and aggregation of specific proteins. Amyotrophic lateral sclerosis (ALS), a lethal disease characterized by progressive degeneration of motor neurons is currently understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within motor neurons that contribute to neurotoxicity. It is well established that misfolded/aggregated proteins such as SOD1 and TDP-43 contribute to the toxicity of motor neurons and play a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, and to a lesser extent TDP-43, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of proteins associated with ALS pathology as well as their possible mechanisms of transmission.