The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models

Abstract

Heterozygous mutations in the GBA1 gene—encoding lysosomal glucocerebrosidase (GCase)--are the most common genetic risk factor for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, we developed and characterized two mouse models that investigate aSyn pathology in the context of reduced GCase activity. The first model uses constitutive overexpression of wild type human aSyn in the context of the homozygous GCase activity-reducing D409V mutant form of GBA1. While increased aSyn pathology and grip strength reductions are observed in this model, the nigrostriatal system remains largely intact. The second model involves injection of aSyn preformed fibrils (PFFs) into the striatum of the homozygous GBA1 D409V KI model. The GBA1 D409V mutation did not exacerbate pathology induced by aSyn PFF injection. This study sheds light on the relationship between aSyn and GCase in mouse models, highlighting the impact of model design on the ability to model a relationship between these proteins in PD-related pathology.

Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy

“…Furthermore, non-progressive spread 22 or the lack of involvement of crucial upstream/downstream disease pathways might account for the lack of phenotypes observed in PFF models. Our findings support the conclusion that in αsyn PFF models, neither strains from patients with GBA1 mutations nor host murine Gba1 genotype influence seeding efficiency or spread 20,30 . Instead, GBA1 mutations might act upstream on the endogenous αsyn pool creating a cellular environment conducive to αsyn misfolding and aggregation 20,31,34 .…”

“…Several recent reports have investigated whether GBA1 mutations influence αsyn PFF seeding behavior with conflicting conclusions 20,[29][30][31][32] . Here we took the unique approach of assessing both host-genotype and unique αsyn PFF polymorphs to account for the aggressive clinical outcomes seen in GBA-PD.…”

“…GBA1 D409V KI mice have reduced GCase activity and accumulation of glycosphingolipid in the brain and liver 19 . Although de novo αsyn pathology is not observed in the brain of these mice 19 , they are more susceptible to αsyn accumulation 20 , have increased αsyn expression at 12 months of age 20,21 , and show enhanced spread via increased exocytosis of αsyn 21 .…”

Live cell in situ lysosomal GCase activity correlates to alpha-synuclein levels in human differentiated neurons with LRRK2 and GBA1 mutations

“…Studies using cells to introduce pathogenic GBA1 mutations or modulate GCase activity through knockdown or inhibition have shown increased levels of alpha-synuclein (Bae et al, 2014 ; Papadopoulos et al, 2018 ; Maor et al, 2019 ; Navarro-Romero et al, 2022 ). Furthermore, increased alpha-synuclein pathology is observed in mouse models with GCase dysfunction (Migdalska-Richards et al, 2020 ; Polinski et al, 2022 ). Exactly how GCase activity causes the accumulation of alpha-synuclein remains to be determined, but it likely involves the impairment of autophagy pathways, in particular chaperone-mediated autophagy (Kuo et al, 2022 ).…”

Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase

“…The relationship between PD-linked GCase mutations and ASYN spreading has been assessed by a relatively small number of in vivo studies. In these studies, induction of ASYN pathology and its progressive brain propagation were achieved by intraparenchymal administration of pathogenic pre-formed ASYN fibrils (PFFs) [20][21][22][23] . PFFs were injected, for example, unilaterally or bilaterally into the striatum of L444P/wt mice or unilaterally into the olfactory bulb of mice carrying a heterozygous D409V mutation of Gba1.…”