Eid, Thamir Mahmoud; (2022) Synaptic Dysfunction in Alpha-Synucleinopathies Associated with Glucocerebrosidase (GBA) Mutation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parkinson’s disease (PD) is a progressive neurodegeneration with an array of motor and non-motor symptoms. Mutations in glucocerebrosidase gene (GBA) have been recognised as a risk factor for developing PD and Lewy body dementia (LBD) including Parkinson’s disease with dementia (PDD) and dementia with Lewy body (DLB). One of the most common GBA mutations is N370S. A total of 119 neuropathologically confirmed PD cases from QSBB were screened for known GBA variations. From the 15 newly found GBA cases, those with N370S were included in the cohort of 10 controls, 7 PD/LBD with GBA N370S, and 20 PD/LBD without GBA mutations to investigate eleven synaptic proteins in prefrontal, temporal, anterior cingulate (ACC), and parietal cortices. I observed significant regional alteration in pre-synaptic, post-synaptic, and astrocytic proteins between diseased groups versus controls. The GBA cases showed significantly altered expression of specific synaptic proteins compared with WT, suggesting different mechanisms underlying PD pathogenesis. Subsequently, I investigated the alpha synuclein (α-syn) burden in prefrontal and anterior cingulate cortices between same cohorts and, similar to previous work, found increased α-syn in both PD/LBD groups compared with controls. Finally, immunohistochemical staining of four novel epitope specific α-syn antibodies and one recognises the phosphorylation site of α-syn antibody was performed in ACC, substantia nigra, and ventral tegmental area between PD/LBD with GBA N370S and PD/LBD WT. The analysis revealed that different species of α-syn were significantly increased in PD/LBD with GBA mutation compared with PD/LBD WT in different regions. This suggests that GBA mutations particularly N370S increase the spread of α-syn pathology and thus potentially lead to the early disease onset, increased cognitive decline, and rapid disease progression in GBA carriers Overall, my data demonstrates for the first time a large immunoblot screen of synaptic markers in synucleinopathies associated with GBA mutations in different postmortem brain regions. My study provides further insight into the role of GBA in α-syn accumulation, and into underlying mechanisms when targeting GBA for treatment of PD.

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