Abstract
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1+/−) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1+/− carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1+/− carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1c.1276_1298del), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1c.1276_1298del mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1c.1276_1298del zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.
Highlights
Gaucher’s disease (GD) is the most common lysosomal storage disorder with a prevalence of 1:40 000 [1]
The genetic loci of both glucocerebrosidase 1 (GBA1) and (Danio rerio) gba1 shared conserved synteny, both containing the genes RUSC1, FDPS and DAP3 within 500 kb of each orthologue. gba1 was expressed at constant levels through 1–5 dpf with more marked expression in the brain
Expression was detected in adult brain and liver tissue, organs affected by GD pathology (Fig. 1A–D)
Summary
Gaucher’s disease (GD) is the most common lysosomal storage disorder with a prevalence of 1:40 000 [1]. It is caused by autosomal recessively inherited homozygous or compound heterozygous mutations in glucocerebrosidase 1 (GBA1). GBA1 is a lysosomal enzyme required for the breakdown of glucosylceramide to ceramide and glucose and forms part of the sphingolipid pathway. Current treatment options largely focus on enzyme replacement therapy, which is effective for the treatment of non-neurological complications of GD but ineffective for the treatment or prevention of neurological complications due to its inability to cross the blood–brain barrier [3]
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