Journal Article

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

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

2021

Overview

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 shortchain 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.

• Publisher: National Academy of Sciences
• Subject: Accumulation / Agglomeration / alpha-Synuclein - chemistry / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Amino Acid Sequence / Animals / Biological Sciences / Brain - drug effects / Brain - metabolism / Cathepsins / Cathepsins - metabolism / Cell Differentiation / Dementia disorders / Depletion / Gaucher's disease / Genetic variability / Glucosylceramidase / Glycosphingolipids - chemistry / Glycosphingolipids - metabolism / Humans / Induced Pluripotent Stem Cells - drug effects / Induced Pluripotent Stem Cells - physiology / Inositol - analogs & derivatives / Inositol - toxicity / Lewy bodies / Lysosomes - metabolism / Mesencephalon / Mice / Movement disorders / Mutation / Neonates / Neurodegeneration / Neurodegenerative diseases / Neurological complications / Neuroscience / Oligomers / Parkinson's disease / Pathology / Phenotypes / Physiology / Risk analysis / Risk factors / Substrates / Synuclein / Time Factors