Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo.
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.
['Fredriksen|Kristina|K|https://orcid.org/0000-0001-6366-8428', 'Aivazidis|Stefanos|S|', 'Sharma|Karan|K|', 'Burbidge|Kevin J|KJ|https://orcid.org/0000-0003-1055-0199', 'Pitcairn|Caleb|C|', 'Zunke|Friederike|F|', 'Gelyana|Eilrayna|E|', 'Mazzulli|Joseph R|JR|']
glycosphingolipids Gaucher disease α-synuclein Parkinson’s disease lysosomal storage disease