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

Kristina Fredriksen, Stefanos Aivazidis, Karan Sharma, Kevin J. Burbidge, Caleb Pitcairn, Friederike Zunke, Eilrayna Gelyana, Joseph R. Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere2108489118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 14 2021


  • Gaucher disease
  • Parkinson’s disease
  • glycosphingolipids
  • lysosomal storage disease
  • α-synuclein

ASJC Scopus subject areas

  • General


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