Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo

Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2108489118. doi: 10.1073/pnas.2108489118.

Abstract

GBA1 mutations that encode lysosomal β-glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher disease (GD) and are strong risk factors for synucleinopathies, including Parkinson's disease and Lewy body dementia. Only a subset of subjects with GBA1 mutations exhibit neurodegeneration, and the factors that influence neurological phenotypes are unknown. We find that α-synuclein (α-syn) neuropathology induced by GCase depletion depends on neuronal maturity, the physiological state of α-syn, and specific accumulation of long-chain glycosphingolipid (GSL) GCase substrates. Reduced GCase activity does not initiate α-syn aggregation in neonatal mice or immature human midbrain cultures; however, adult mice or mature midbrain cultures that express physiological α-syn oligomers are aggregation prone. Accumulation of long-chain GSLs (≥C22), but not short-chain species, induced α-syn pathology and neurological dysfunction. Selective reduction of long-chain GSLs ameliorated α-syn pathology through lysosomal cathepsins. We identify specific requirements that dictate synuclein pathology in GD models, providing possible explanations for the phenotypic variability in subjects with GCase deficiency.

Keywords: Gaucher disease; Parkinson’s disease; glycosphingolipids; lysosomal storage disease; α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cathepsins / metabolism
  • Cell Differentiation
  • Glycosphingolipids / chemistry*
  • Glycosphingolipids / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / physiology
  • Inositol / analogs & derivatives
  • Inositol / toxicity
  • Lysosomes / metabolism
  • Mice
  • Time Factors
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Glycosphingolipids
  • alpha-Synuclein
  • Inositol
  • Cathepsins
  • conduritol epoxide