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<p>Mutations in the <i>ATP13A2</i> gene were identified as the cause of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of Parkinson’s disease (PD). Developing relevant and predictive models for the rare PD forms is necessary to understand the pathological mechanisms and validate therapeutic strategies. Herein, we aimed to comprehensively characterize the first transgenic <i>Atp13a2</i> knockout rat model. Behavioral assessment demonstrated specific developmental deficits in animals with deletion of <i>Atp13a2</i>. Further analysis revealed that <i>Atp13a2</i> knockout rats displayed age-dependent fine motor skills deficits and impaired locomotor habituation similar to those observed in PD patients at the early stage of motor symptoms. In contrast, no change in the nigrostriatal integrity was observed. An extended investigation on heavy metals homeostasis, autophagy-related markers, and lipofuscin accumulation showed significant changes reminiscent of KRS. Finally, we tested whether inducing pathology by viral-mediated overexpression of human α-synuclein or human tyrosinase exacerbated the onset or extent of pathological changes. This <i>Atp13a2</i> KO rat model could help better understand autophagy in PD pathogenesis and open new therapeutic validation opportunities.</p>

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Phenotypic characterization of an Atp13a2 knockout rat model of Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Rémi Kinet,
  • Joanna Sikora,
  • Marie-Laure Arotcarena,
  • Melina Decourt,
  • Eric Balado,
  • Evelyne Doudnikoff,
  • Sylvain Bohic,
  • Marta Vesnaver,
  • Anna Lovisotto,
  • Marie-Laure Thiolat,
  • Nathalie Dutheil,
  • Claire Mazzocco,
  • Karim Harhouri,
  • Rémy Steinschneider,
  • Severine Menoret,
  • Laurent Tesson,
  • Ignacio Anegon,
  • Michele Morari,
  • Miquel Vila,
  • François Georges,
  • Erwan Bezard,
  • Pierre-Olivier Fernagut,
  • Benjamin Dehay

摘要

Mutations in the ATP13A2 gene were identified as the cause of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of Parkinson’s disease (PD). Developing relevant and predictive models for the rare PD forms is necessary to understand the pathological mechanisms and validate therapeutic strategies. Herein, we aimed to comprehensively characterize the first transgenic Atp13a2 knockout rat model. Behavioral assessment demonstrated specific developmental deficits in animals with deletion of Atp13a2. Further analysis revealed that Atp13a2 knockout rats displayed age-dependent fine motor skills deficits and impaired locomotor habituation similar to those observed in PD patients at the early stage of motor symptoms. In contrast, no change in the nigrostriatal integrity was observed. An extended investigation on heavy metals homeostasis, autophagy-related markers, and lipofuscin accumulation showed significant changes reminiscent of KRS. Finally, we tested whether inducing pathology by viral-mediated overexpression of human α-synuclein or human tyrosinase exacerbated the onset or extent of pathological changes. This Atp13a2 KO rat model could help better understand autophagy in PD pathogenesis and open new therapeutic validation opportunities.