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bioRxiv · 10.1101/2023.08.24.554646

Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb.

Killinger, B.·Kordower, J. H.·Walton, S.·Fenyi, A.·Tittle, T.·Choi, S.·Sidransky, E.·Paul, G.·Melki, R.
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Abstract

Parkinsons disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (syn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote syn spread or drive the generation of highly pathogenic syn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human -syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several syn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-syn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and syn strain had little effect on overall seeding efficacy and global PSER129-interactions.

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Killinger, B., Kordower, J. H., Walton, S., Fenyi, A., Tittle, T., Choi, S., Sidransky, E., Paul, G., Melki, R.. 2023-08-25. Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb.. https://doi.org/10.1101/2023.08.24.554646

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