Loss of GBA in zebrafish leads to dopaminergic neurodegeneration, but overexpression of α-synuclein does not further worsen degeneration

Abstract

ObjectivesParkinson's disease is a neurodegenerative disorder that causes motor and nonmotor symptoms due to the loss of dopaminergic nerves and is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein. Glucosylceramidase beta (GBA), which is a causative gene of autosomal recessive Gaucher disease, is also known to be a risk gene for Parkinson's disease. In this study, we tried to detect synergistic effects of α-synuclein accumulation and gba depletion on dopaminergic neurodegeneration in zebrafish. MethodsWe generated a transgenic line of zebrafish overexpressing the A53T α-synuclein and gba mutant fish, and analyzed pathologies of α-synuclein aggregation and neurodegeneration.Results Zebrafish overexpressing the A53T α-synuclein did not exhibit α-synuclein aggregate formation. After the loss of gba function in this mutant α-synuclein transgenic line, we observed the marked presence of α-synuclein aggregates. Loss of gba function in zebrafish resulted in dopaminergic and noradrenergic neurodegeneration but this level of neurodegeneration was not exacerbated by overexpression of mutant α-synuclein. ConclusionsThese results indicate that loss of gba function was sufficient to generate a neurodegenerative phenotype in zebrafish regardless of the expression of α-synuclein.

Modeling familial and sporadic Parkinson's disease in small fishes

“…In zebrafish, one study found no presence of α‐synuclein aggregation nor DA neuron degeneration in a transgenic line expressing human α‐synuclein A53T (Kodera et al, 2022). Another study reported that transgenic lines expressing wild‐type and A53T human α‐synuclein exhibited a slight reduction of life span, an increase in apoptotic cell death, and impaired axonal mitochondrial transport (Lopez et al, 2022).…”

“…In zebrafish, Gba knockout resulted in DA neuron neurodegeneration. α‐Synuclein aggregation pathology was induced when these fish were crossed with human α‐synuclein A53T transgenic fish, but the level of neurodegeneration was not exacerbated (Kodera et al, 2022). Therefore, in zebrafish, the association between Gba deficiency and neurodegeneration may be α‐synuclein‐independent.…”