Objective:

To determine whether mutations in the gene beta-glucocerebrosidase 1 (GBA1), the strongest genetic risk factor for PD, promote tau and TDP-43 co-pathology alongside Lewy body pathology.

Background: GBA1 mutations are associated with faster cognitive and motor decline and increased cognitive behavioral symptoms. Because cellular pathways involved in tau and a-synuclein (a-syn) pathogenic aggregation overlap, we hypothesize that GBA1 mutations promote tau and TDP-43 co-pathology.

Method: Human induced pluripotent stem cells (iPSCs) were generated from an individual with PD carrying the IVS2+1G>A GBA1 variant (GBA1^IVS). Dopaminergic neurons were differentiated from GBA^IVS and matched healthy control iPSCs. Neurons were stained with antibodies for hyperphosphorylated tau (p-tau with AT8 antibody), aggregated a-syn, or TDP-43, and markers for endolysosomal trafficking. Neurons were also infected with lentivirus to express fluorescently tagged a-syn and tau to observe co-pathology in real time. Imaris software 3D reconstructed z-stacks and measured endolysosomal vesicles and subcellular localization of tau and TDP-43. Lysates of recipient cells were analyzed by Western blot. We are also quantifying co-pathology in post-mortem tissue of GBA1-carriers compared to non-GBA1 carriers matched by age, sex, ApoE status and a-syn Braak stage across multiple brain regions.

Results: We observed phospho-Ser129-a-syn, p-tau, and aggregated a-syn in GBA1^IVS neurons but not control neurons. GBA1deficient neurons also showed increased cytoplasmic tau and TDP-43, while control neurons had increased nuclear localization of these proteins. The UW ADRC Precision Neuropathology Core has 14 well-characterized brain donors with GBA1 variants, matched to 14 brain donors with similar age and Braak staging who do not carry GBA1 variants. enabling comparison of Lewy and tau pathology across multiple brain regions using unbiased digital histopathological quantification.

Conclusion: Our iPSC-neurons suggest that GBA1 deficiency drives tau and TDP-43 co-pathology in addition to Lewy body pathology. Live cell imaging will clarify how GBA1 deficiency alters intracellular trafficking of tau and a-syn. Neuropathologic analysis will determine whether GBA1 deficiency increases co-pathology burden and whether specific brain regions are more susceptible. Together, these studies will elucidate early mechanisms driving co-pathology in the PD brain.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba1-deficiency-promotes-tau-and-tdp-43-co-pathology/