Pathological alpha-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of alpha-syn in vivo
Fredriksen K, Aivazidis S, Sharma K, Burbidge KJ, Pitcairn C, Zunke F, Gelyana E, Mazzulli JR (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 118
Journal Issue: 50
Abstract
GBA1 mutations that encode lysosomal beta-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 alpha-synuclein (alpha-syn) neuropathology induced by GCase depletion depends on neuronal maturity, the physiological state of alpha-syn, and specific accumulation of long-chain glycosphingolipid (GSL) GCase substrates. Reduced GCase activity does not initiate alpha-syn aggregation in neonatal mice or immature human midbrain cultures; however, adult mice or mature midbrain cultures that express physiological alpha-syn oligomers are aggregation prone. Accumulation of long-chain GSLs (>= C22), but not short-chain species, induced alpha-syn pathology and neurological dysfunction. Selective reduction of long-chain GSLs ameliorated alpha-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.
Authors with CRIS profile
Involved external institutions
United States (USA) (US)How to cite
APA:
Fredriksen, K., Aivazidis, S., Sharma, K., Burbidge, K.J., Pitcairn, C., Zunke, F.,... Mazzulli, J.R. (2021). Pathological alpha-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of alpha-syn in vivo. Proceedings of the National Academy of Sciences of the United States of America, 118(50). https://doi.org/10.1073/pnas.2108489118
MLA:
Fredriksen, Kristina, et al. "Pathological alpha-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of alpha-syn in vivo." Proceedings of the National Academy of Sciences of the United States of America 118.50 (2021).
BibTeX: Download