Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

TLDR

Amyotrophic lateral sclerosis is linked to mutations and misfolding of Cu/Zn superoxide dismutase, and mutant misfolded SOD1 can convert wild‑type SOD1 into a misfolded form in a prion‑like manner. Transmission of misfolded SOD1 between cells occurs via release and uptake of protein aggregates or through small membrane‑bounded vesicles known as exosomes. Misfolded wild‑type SOD1 can be transmitted from cell to cell and perpetuate protein misfolding, providing a mechanism that may explain the systematic spread of sporadic ALS.

Abstract

Significance Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) SOD1 to a misfolded form inside living cells in a prion-like fashion. We now report that misfolded WT SOD1 can be transmitted from cell to cell, and that propagated protein misfolding can be perpetuated. Misfolded SOD1 transmission between cells can be mediated through release and uptake of protein aggregates or via small membrane-bounded transport vesicles called exosomes. These mechanisms may help explain why sporadic ALS, without a known genetic cause, can spread systematically from region to region in a progressive manner.