Objective: To investigate the pathological substrate of impaired cognition in Parkinson’s disease (PD) associated with glucocerebrosidase (GBA) mutation.

Background: Mutations in glucocerebrosidase gene (GBA), originally implicated in Gaucher’s disease, have been recognized as a risk factor in PD. These mutations also increase the risk of developing Lewy body dementia which includes dementia with Lewy bodies (DLB) and PD dementia (PDD). Currently, there is no clear understanding of the mechanistic relationships between GBA mutations and DLB/PDD, although, synaptic protein changes have been shown to correlate with cognitive change in AD (Masliah et al., 2001, Vallortigara et al., 2016) and DLB/PDD (Whitfield et al., 2014, Vallortigara et al., 2016, Bereczki et al., 2016, 2018).

Method: Brain tissue was obtained from the Queen Square and South West Dementia Brain Banks including cases with GBA mutations. DNA was extracted from 119 PD cases and screened to identify additional GBA mutations. Next synaptic markers were examined in prefrontal and cingulate cortices brain homogenates of 10 controls, 11 DLB/PDD and 9 non-demented PD cases. PD with GBA mutations (N370S) were selected and divided into demented (n=3) and non-demented (n=4). . Selected synaptic proteins (synaptophysin, SNAP25, PSD95, neurogranin, Rab3a, VAMP2) and an astrocytic protein (VAMP3) were assayed using western blotting.

Results: 15 GBA mutation cases including 1 with, N370S were found. Post-synaptic proteins, PSD95 and neurogranin were unchanged in any of the groups in either cortical region. Presynaptic proteins, synaptophysin, SNAP25, RAB3A and VAMP2 also did not show any significant change in the subgroups compared to control. The astrocytic protein VAMP3 was significantly reduced in PD WT (p= 0.0106) compared with control and DLB/PDD in prefrontal cortex. VAMP3 was also significantly (p = 0.0265) reduced in both PD WT and DLB/PDD WT compared to both of the GBA groups but remained unchanged compared with controls in cingulate cortex.

Conclusion: Our GBA cases show no change in any of the synaptic proteins investigated compared with control suggesting that synaptic changes are unlikely to underlie cognitive impairment in PD with GBA mutation. In contrast, VAMP3 levels in astrocytes may be important in the pathology of PD.

References: (Masliah et al., 2001, Whitfield et al., 2014, Vallortigara et al., 2016, Bereczki et al., 2016, 2018).

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/synaptic-function-in-parkinsons-disease-associated-with-gba-mutations/