Obensa Bertroli, Clara; (2024) Glucocerebrosidase dysfunction results in increased membrane binding and aggregation propensity of α-synuclein in Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London).

Text Obensa Bertroli_10199661_thesis.pdf Access restricted to UCL open access staff until 1 December 2025. Download (12MB)

Abstract

Glucosylceramidase beta 1 (GBA1) mutations are the major genetic risk factor for developing Lewy body (LB) diseases, including Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal enzyme acid β-glucosidase (GCase), which catalyses glucosylceramide (GlcCer) hydrolysis into glucose and ceramide. A core hallmark of LB diseases is lipid dyshomeostasis. Recent evidence shows that LBs are mainly composed of membranous structures interspaced with sparse α-synuclein (αSyn) fibrils, reinforcing the link between enhanced αSynlipid interactions and pathology. Cellular lipid composition is one of the main factors influencing the interaction of αSyn with membranes. Therefore, we hypothesised that GCase dysfunction, by altering lipid homeostasis, promotes αSyn aggregation by stabilising its interaction with membranes. Using human GBA1 D409V/WT and GBA1 knock-out (KO) induced pluripotent stem cell (iPSC)-derived cortical neurons, we demonstrated that GCase loss-of-function stabilises αSyn at membranes, prompting αSyn to seed-induced aggregation. This was validated in post-mortem brain tissue from sporadic PD patients by reporting an association between GCase loss-of-function, increased αSyn-membrane binding and LB pathology. We further showed that ceramide deficiency due to GCase dysfunction leads to enhanced αSyn membrane interactions in GBA1 D409V/WT iPSC-derived neurons. Treatment of these neurons with carmofur to inhibit ceramide degradation decreased membrane-bound αSyn levels, protecting against αSyn seed-induced aggregation. Finally, we showed that cathepsin D impairment may be a modulator of the pathological accumulation of αSyn at membranes downstream GCase dysfunction. These findings provide novel insights into the role of GCase in αSyn aggregation and suggest that GCase dysfunction might be leading to membrane-rich LBs through ceramide deficiency in PD. This points towards the regulation of ceramide levels as a potential effective therapeutic strategy to prevent membrane-induced αSyn aggregation in PD.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item