PIK3CA gain-of-function mutation in Schwann cells leads to severe neuropathy and aerobic glycolysis through a non-cell autonomous effect

• 成果类型: Article
• 署名作者: Venot, Quitterie; Firpion, Marina; Ladraa, Sophia; Bayard, Charles; Magassa, Sato; Di Guardo, Roberta; Fraissenon, Antoine; Hoguin, Clement; Protic, Sanela; Morin, Gabriel; Mayeux, Franck; Gourdon, Genevieve; Fraitag, Sylvie; Balducci, Estelle; Kaltenbach, Sophie; Villarese, Patrick; Asnafi, Vahid; Viel, Thomas; Autret, Gwennhael; Tavitian, Bertrand; Goudin, Nicolas; Guibaud, Laurent; Bolino, Alessandra; Canaud, Guillaume
• 署名单位: Universite Paris Cite; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; CHU Lyon; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute for Engineering & Systems Sciences (INSIS); Institut National des Sciences Appliquees de Lyon - INSA Lyon; CHU de St Etienne; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Vita-Salute San Raffaele University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14521
• DOI: 10.1073/pnas.2424867122
• 发表日期: 2025-07-01
• 关键词: myelination; expression; GROWTH; pten

摘要

PIK3CA-related disorders are rare genetic disorders due to somatic gain-of-function mutations in PIK3CA during embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients with PIK3CA-related disorders indicates that peripheral nerves are frequently affected, leading to severe neurological symptoms. However, the exact underlying mechanism of these disorders remains unclear. To address this, we developed a mouse model with a PIK3CA gain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed that PIK3CA-mutated cells communicate with neighboring healthy cells, such as adipocytes and hair follicles, through a unique crosstalk mechanism that triggers their growth, proliferation, and anagen phase expansion. Additionally, we demonstrated that PIK3CA mutation in peripheral nerves leads to a metabolic shift through glycolytic activation. We investigated the effects of alpelisib, an approved pharmacological inhibitor of PIK3CA, in the model. Early administration of alpelisib significantly improved the signs and symptoms in the mice. However, when treatment was delayed, its efficacy was diminished due to the drug's inability to penetrate the myelin sheath effectively. In summary, our study offers a valuable mouse model for studying PIK3CA-related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.