Phenotypic diversity in ALS and the role of poly-conformational protein misfolding

Abstract

In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype.

Keywords: Amyotrophic lateral sclerosis; Prion; Strains; Superoxide dismutase-1; TDP-43.

Fig. 1.

Distinct pathologies induced in G85R-SOD1:YFP inoculated mice. Images of spinal cords from diseased G85R-SOD1:YFP mice injected within their spinal cords at P0 with the first or second passages of the indicated homogenates. Significant differences were observed among those G85R-SOD1:YFP inclusions induced by homogenates from diseased G93A expressing mice versus those induced by recWT fibrils. These differences were retained among secondary passaging and is a strong indication of SOD1 conformational templating. Reprinted by permission from Springer Nature Customer Service Centre GmbH: [Springer] [Acta Neuropathologica] (Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS, Ayers, J.I., et al., 2016 [6]

Fig. 2.

Alternative folding pathways for G85R-SOD1 fALS missense point mutant of SOD1 exposed to misfolded SOD1 seeds. Human G85R-SOD1 exhibits defects in the binding of Zn and Cu (indicated by grayed out Cu) that destabilize native structure [26]. A subset of G85R-SOD1 subunits can acquire Zn and Cu and achieve near native conformation. Immature mutant SOD1 exposed to different SOD1 seed aggregates is susceptible to conformational templating, leading to alternative conformations of misfolded protein. In the example here, seeding with fibrils of recombinant (recWT) WT SOD1 produce a strain that forms fibrillar inclusion pathology while seeding with spinal cord homogenates from paralyzed G93A mice induces punctate pathology [6]. A similar type of diagram could be drawn for G85R SOD1 seeded with tissue homogenates from paralyzed G85R-SOD1 mice (Strain 1) and spinal homogenates from paralyzed D90A-SOD1 mice (Strain 2) [17].