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<p>Young-onset Parkinson’s disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in <i>Parkin</i> (<i>PRKN</i>). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of <i>PRKN</i>-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9 vectors with different promoters were engineered to deliver <i>PRKN</i> cDNA with efficient human Parkin (hParkin) expression in dopaminergic (DA) neurons as shown in <i>PRKN</i>-null human induced pluripotent stem cell (iPSC) derived DA neurons. Further, we show that AAV9-<i>PRKN</i> treatment can protect nigral DA neurons in two mouse PD models, the 6-hydroxydopamine (6-OHDA)-lesion and the α-synuclein (α-Syn) pre-formed fibrils (PFFs)-lesion model. In summary, AAV9-<i>PRKN</i> gene therapy demonstrates neuroprotective properties and may represent a promising approach for <i>PRKN</i>-PD, with potential broader applications in idiopathic PD and other neurodegenerative diseases.</p>

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In vitro and in vivo rescue of dopaminergic neurons in Parkinson’s disease models after Parkin gene therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Takeshi Hioki,
  • Masaaki Nishimura,
  • Xiuxia Sun,
  • Sarah Melissa Jacobo,
  • Miyu Nakayama,
  • Mitsuhiro Nishihara,
  • Kimio Tohyama,
  • Po-Ting Liu,
  • Takuro Okai,
  • Maiko Tanaka,
  • Gabriele Proetzel

摘要

Young-onset Parkinson’s disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9 vectors with different promoters were engineered to deliver PRKN cDNA with efficient human Parkin (hParkin) expression in dopaminergic (DA) neurons as shown in PRKN-null human induced pluripotent stem cell (iPSC) derived DA neurons. Further, we show that AAV9-PRKN treatment can protect nigral DA neurons in two mouse PD models, the 6-hydroxydopamine (6-OHDA)-lesion and the α-synuclein (α-Syn) pre-formed fibrils (PFFs)-lesion model. In summary, AAV9-PRKN gene therapy demonstrates neuroprotective properties and may represent a promising approach for PRKN-PD, with potential broader applications in idiopathic PD and other neurodegenerative diseases.