Glucocerebrosidase 1 deficientDanio reriomirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death

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.

Association ofGBAMutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

“…32 Recent work in animal and cell culture models of glucocerebrosidase deficiency suggests that GBA mutations lead to impaired degradation of misfolded proteins through disruption of autophagic flux, resulting in accumulation of α-synuclein. 33–36 It is possible that GBA influences different molecular pathways at different stages of PD.…”

Genetically engineered animal models of Parkinson's disease: From worm to rodent

“…While several zebrafish models overexpressing the human Parkin, DJ‐1 or PINK1 (WT and mutant), as well as KO of the ortholog genes have been developed (Table ), the presence of zsyn aggregates has never been reported in any of them. Interestingly, ubiquitin‐positive but syn‐negative inclusions have been detected in heterozygous GBA KO zebrafish (Keatinge et al., ).…”

Mitochondrial Dysfunction in Lysosomal Storage Disorders

“…On the other hand, the GBA KO Zebrafish ( Danio rerio ) model presented mitochondrial dysfunction and reduced autophagic flux, deterioration of the activity of complexes III and IV of mitochondrial ETC, and reduced protein expression of complex I (subunit NDUFA9) and IV (Cox4i1) [49]. iPSC-differentiated Gaucher type II neurons also showed mitochondrial dysfunction, reduced autophagic flux, and accumulation of autophagosomes [47].…”