ALS-linked mutant SOD1 proteins promote A beta aggregates in ALS through direct interaction with A beta

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-beta (A beta) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular AS specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons. In this study, we have demonstrated that the A beta-binding region is exposed on the SOD1 surface through the conformational changes due to misfolding of SOD1. Interestingly, we found that the intracellular aggregation of A beta is enhanced through the direct interaction of A beta with the A beta-binding region exposed to misfolded SOD1. Ultimately, increased A beta aggregation by this interaction promotes neuronal cell death. Consistent with this result, A beta aggregates was three-fold higher in the brains of G93A transgenic mice than those of non Tg. Our study provides the first direct evidence that A beta, an AD-linked factor, is associated to the pathogenesis of ALS and provides molecular clues to understand common aggregation mechanisms in the pathogenesis of neurodegenerative diseases. Furthermore, it will provide new insights into the development of therapeutic approaches for ALS. (C) 2017 Elsevier Inc. All rights reserved.