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<p>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 <i>acmsd</i> deficiency with marked increase in quinolinic acid. Despite this, <i>acmsd</i><sup><i>-/-</i></sup> 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 <i>cxcl8, il-1β</i>, and <i>mmp9</i> were similar between <i>acmsd</i><sup><i>-/-</i></sup> 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 <i>acmsd</i><sup><i>-/-</i></sup> 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.</p>

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A zebrafish model of acmsd deficiency does not support a prominent role for ACMSD in Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月9日

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  • Emma Fargher,
  • Marcus Keatinge,
  • Oluwaseyi Pearce,
  • Petteri Piepponen,
  • Pertti Panula,
  • Fredericus J. M. van Eeden,
  • Ryan B. MacDonald,
  • Oliver Bandmann

摘要

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.