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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  ( gba1 c.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.  gba1 c.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 &gt;30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This  gba1 c.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.

human molecular genetics

Glucocerebrosidase 1 deficient  Danio rerio  mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death