Prognostic role of “prion-like propagation” in SOD1-linked familial ALS: an alternative view

Abstract

“Prion-like propagation” has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS – its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.

Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model

“…Misfolded protein aggregation is a major pathological feature of ALS, which is detected in spinal cord even at the presymptomatic stage, and may propagate via cell‐to‐cell transmission . Accumulation of mutant SOD1 aggregates has been proposed to result in MNs loss by gain of function toxicity and inhibition of a multitude of cellular function including axonal transport, mitochondrial function, and protein homeostasis .…”

ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad

“…In fact they may be a neuroprotective phenomenon, as monomeric and oligomeric misfolded ALS proteins seem to be toxic to MNs (Guo et al, 2010 ). Monomeric and oligomeric misfolded proteins in turns may exert the actual toxicity in ALS according to recent findings suggesting a “prion-like” focal propagation of the disease (Polymenidou and Cleveland, 2011 ; Sugaya and Nakano, 2014 ). In support of that mutant and wild-type SOD1 have been found to spontaneously fibrillize (Grad et al, 2011 ; Munch et al, 2011 ) and both TDP-43 and FUS were proposed to contain a prion-like glutamine/asparagine (Q/N)-rich domain found in inclusions.…”

Mutations in Superoxide Dismutase 1 (Sod1) Linked to Familial Amyotrophic Lateral Sclerosis Can Disrupt High-Affinity Zinc-Binding Promoted by the Copper Chaperone for Sod1 (Ccs)

“…While all of the fALS-Sod1 mutations lead to the same disease and outcome, the rates of disease progression vary widely between mutations [24,25]. A4V is the most common mutation in North America, accounting for 50% of Sod1-linked fALS cases [26].…”