Abstract
Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher’s disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson’s disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms and novel therapeutic approaches, as well as to elucidate the molecular mechanisms leading to enhanced PD risk in GBA1 mutation carriers. The aim of this study was to develop and characterize a novel GBA1 mouse model and to facilitate wide accessibility of the model with phenotypic data. Herein we describe the results of molecular, biochemical, histological, and behavioral phenotyping analyses in a GBA1 D409V knock-in (KI) mouse. This mouse model exhibited significantly decreased GCase activity in liver and brain, with substantial increases in glycosphingolipid substrates in the liver. While no changes in the number of dopamine neurons in the substantia nigra were noted, subtle changes in striatal neurotransmitters were observed in GBA1 D409V KI mice. Alpha-synuclein pathology and inflammation were not observed in the nigrostriatal system of this model. In summary, the GBA1 D409V KI mouse model provides an ideal model for studies aimed at pharmacodynamic assessments of potential therapies aiming to restore GCase.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease and PD is the most common movement disorder
While we focused our phenotyping studies predominately on mice homozygous for the GBA1 D409V KI mutation, we investigated effects in mice heterozygous for the same mutation to interrogate potential gene dosing effects and because PD patients with GBA1 mutations are typically heterozygous
To investigate potential gene dosing effects of GBA1 D409V KI and because PD patients with mutations in the GBA1 gene tend to be heterozygous, we examined GCase activity and GSL levels in mice heterozygous for the GBA1 D409V KI mutation compared to wild type (WT) mice, using the same methodology deployed at Amicus for analyses of hom GBA1 D409V KI mice
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease and PD is the most common movement disorder. The etiology of Parkinson’s disease involves complex gene-environment interactions on the background of aging. Mutations in the gene GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase), have been linked to PD, and are recognized to collectively be the greatest known genetic risk factor for development of idiopathic PD [3]. Decreased GCase activity has been reported in PD patients with and without GBA1 mutations [6]. Accumulating experimental evidence in cell-free systems, cell culture, preclinical animal models, and patient biosamples suggests a correlation between decreased GCase activity and accumulation of the PD-relevant protein alpha-synuclein (aSyn) [7,8,9,10]. GlcSph in Brain SNpc Cell Loss Lysosomal Function aSyn Pathology Inflammation Motor Phenotypes Unaffected by mutation [17] 50–100% of WT [17] 22.5–25% of WT [17, 18] ~2.5% of WT [17]
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