Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model
Abstract
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.
Related
- Immunotherapy restores therapeutic efficacy of fecal microbiome transplants to treat Clostridioides difficile
- Combining pro-resolving therapy with cyclosporine A restores immune homeostasis and reduces toxicity in autoimmune bone marrow failure
- TIM3 Blockade with Hypomethylating Therapy Restores NK Cell and Cytotoxic CD4+ T-cell Activity in Patients with AML or MDS
- FLOT versus SOX as immunochemotherapy backbones for neoadjuvant or conversion therapy in gastric cancer: efficacy, toxicity, and postoperative safety in a real-world cohort
- Efficacy of sound therapy in chronic tinnitus patients with mild hearing loss: a multicentre, double-blind, placebo-controlled randomized clinical trial
BibTeX
@article{cocozza2026gene,
title = {{Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model}},
author = {Germana Cocozza and Tiziano D’andrea and Martina Di Rocco and Ludovica Maria Busdraghi and Gilda Chilà and Xingzi Lin and Enrico Lanza and Fanny Collaud and Francesca Follo and Clelia Buccheri and Viola Folli and Giuseppe Ronzitti and Ferdinando Scavizzi and Marcello Raspa and Vincenzo Leuzzi and Vladimir Katanaev and Serena Galosi and Sergio Fucile and Simone Martinelli and Giuseppina D’alessandro and Cristina Limatola},
journal = {Acta Neuropathologica Communications},
year = {2026},
month = jul,
doi = {10.1186/s40478-026-02389-6},
url = {https://hal.science/hal-05769425v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model
AU - Germana Cocozza
AU - Tiziano D’andrea
AU - Martina Di Rocco
AU - Ludovica Maria Busdraghi
AU - Gilda Chilà
AU - Xingzi Lin
AU - Enrico Lanza
AU - Fanny Collaud
AU - Francesca Follo
AU - Clelia Buccheri
AU - Viola Folli
AU - Giuseppe Ronzitti
AU - Ferdinando Scavizzi
AU - Marcello Raspa
AU - Vincenzo Leuzzi
AU - Vladimir Katanaev
AU - Serena Galosi
AU - Sergio Fucile
AU - Simone Martinelli
AU - Giuseppina D’alessandro
AU - Cristina Limatola
PY - 2026
DA - 2026/07/01
JO - Acta Neuropathologica Communications
DO - 10.1186/s40478-026-02389-6
UR - https://hal.science/hal-05769425v1
AB - 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.
SN - 2051-5960
ER -