NeuralCipher Research overview
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Single nucleotide polymorphisms adjacent to the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) gene have been associated with Parkinson's disease (PD) in genome-wide association studies (GWAS). However, its biological validation as a PD risk gene has been hampered by the lack of available models. Using CRISPR/Cas9, we generated a zebrafish model of acmsd deficiency with marked increase in quinolinic acid. Despite this, acmsd-/- zebrafish were viable, fertile, morphologically normal and demonstrated no abnormalities in spontaneous movement. In contrast to the postulated pro-immune pathomechanism linking ACMSD to PD, microglial cells and expression of the proinflammatory cytokines cxcl8, il-1β, and mmp9 were similar between acmsd-/- and controls. The number of ascending dopaminergic neurons, and their susceptibility to MPP+, was also indistinguishable. An upregulation of kynurenine aminotransferase activity was identified in acmsd-/- zebrafish which may explain the absence of neurodegenerative phenotypes. Our study highlights the importance of biological validation for putative GWAS hits in suitable model systems.
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