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<p>The heterotrimeric G proteins are ubiquitous membrane-bound complexes specialized in the transduction of receptor-mediated extracellular signals into intracellular responses. Mutations in the G protein subunit alpha O1 (Gαo), encoded by <i>GNAO1</i>, have been associated with neurodevelopmental disorders characterized by prominent movement disorder with or without epilepsy. The <i>Gnao1</i>[C215Y]/+ mouse model recapitulates key features of the human disease, with a relatively mild phenotype, normal viability and late onset movement abnormalities, detectable in specific motor tasks. Here we report functional alterations in cortical layer V pyramidal neurons from <i>Gnao1</i>[C215Y]/+ mice, with reduction of the inward currents (Ih) and impairment of the GABAB-mediated outward current. We propose an adeno-associated virus (AAV)-based gene therapy aimed at overexpressing the wild-type form of Gαo by intracerebroventricular injection in newborn heterozygous <i>Gnao1</i>[C215Y]/ + mice. Our results demonstrate that overexpression of the wild-type protein mitigates behavioral abnormalities and restores functional neuronal deficits in young adult mice, thereby supporting the development of AAV-mediated gene augmentation strategies to counteract the effects of <i>GNAO1</i> variants in patients. The potential of gene supplementation therapy is further supported by data from genetically modified <i>C. elegans</i> strains carrying not only the relatively mild C215Y variant but also a panel of <i>goa-1</i>/<i>GNAO1</i> mutations associated with more severe phenotypes, suggesting a broader potential of this therapeutic strategy.</p>

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Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Germana Cocozza,
  • Tiziano D’Andrea,
  • Martina Di Rocco,
  • Ludovica Maria Busdraghi,
  • Gilda Chilà,
  • Xingzi Lin,
  • Enrico Lanza,
  • Fanny Collaud,
  • Francesca C. Follo,
  • Clelia Buccheri,
  • Viola Folli,
  • Giuseppe Ronzitti,
  • Ferdinando Scavizzi,
  • Marcello Raspa,
  • Vincenzo Leuzzi,
  • Vladimir L. Katanaev,
  • Serena Galosi,
  • Sergio Fucile,
  • Simone Martinelli,
  • Giuseppina D’Alessandro,
  • Cristina Limatola

摘要

The heterotrimeric G proteins are ubiquitous membrane-bound complexes specialized in the transduction of receptor-mediated extracellular signals into intracellular responses. Mutations in the G protein subunit alpha O1 (Gαo), encoded by GNAO1, have been associated with neurodevelopmental disorders characterized by prominent movement disorder with or without epilepsy. The Gnao1[C215Y]/+ mouse model recapitulates key features of the human disease, with a relatively mild phenotype, normal viability and late onset movement abnormalities, detectable in specific motor tasks. Here we report functional alterations in cortical layer V pyramidal neurons from Gnao1[C215Y]/+ mice, with reduction of the inward currents (Ih) and impairment of the GABAB-mediated outward current. We propose an adeno-associated virus (AAV)-based gene therapy aimed at overexpressing the wild-type form of Gαo by intracerebroventricular injection in newborn heterozygous Gnao1[C215Y]/ + mice. Our results demonstrate that overexpression of the wild-type protein mitigates behavioral abnormalities and restores functional neuronal deficits in young adult mice, thereby supporting the development of AAV-mediated gene augmentation strategies to counteract the effects of GNAO1 variants in patients. The potential of gene supplementation therapy is further supported by data from genetically modified C. elegans strains carrying not only the relatively mild C215Y variant but also a panel of goa-1/GNAO1 mutations associated with more severe phenotypes, suggesting a broader potential of this therapeutic strategy.