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

Keizo Sugaya,Imaharu Nakano

doi:10.3389/fncel.2014.00359

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting motor neurons for which there is no effective treatment
Studies on the clinical course of form of ALS (FALS) suggest that the duration of illness is relatively consistent for each superoxide dismutase 1 (SOD1) mutation, but variable among the different mutations; for example, patients with the A4V mutation survive an average of 1 year after diagnosis, whereas patients with the H46R mutation survive an average of 18 years (Czaplinski et al, 2006)
On the basis of available data for SOD1linked FALS, together with a risk-based modeling approach, we show that prion-like propagation may account for up to 84% of the variability in survival times among subjects with different SOD1 mutations, highlighting the prognostic value of prionlike propagation and providing potential therapeutic targets for SOD1-linked FALS

Summary

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting motor neurons for which there is no effective treatment. Using the stopped-flow technique, Lindberg et al (2004, 2005) reported the effect of protein destabilization ( G) upon ALS-associated point mutations in SOD1 (Byström et al, 2010) Using these date, we performed a regression analysis on the relationship between mean age at disease onset (or respiratory failure death) in patients with different point mutations and the effects of each point mutation on protein destabilization, applying a mathematical model that assumes that toxic species of the misfolded SOD1 are formed via on-pathway nucleation-dependent polymerization: Dimer Unfolded monomer Nucleus → Fibril. Under the assumption that toxic species of misfolded SOD1 are formed via on-pathway nucleation-dependent polymerization, the proportion of intact neurons at time t is largely determined by two integral elements: one reflects the probability distribution function for nucleation lag time (tN), and the other corresponds to an extension time (tE), reflecting the protective effects of aggregate growth attributable to the decreased risk of neuronal cell loss. Be consistent with differences in the ability of SOD1 amyloid conformers with different mutations to cross-seed with normal SOD1

Findings

DISCUSSION

CONCLUSION