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

<i>PIK3CA</i>-related disorders are rare genetic disorders due to somatic gain-of-function mutations in <i>PIK3CA</i> during embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients with <i>PIK3CA</i>-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 <i>PIK3CA</i> gain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed that <i>PIK3CA</i>-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 <i>PIK3CA</i> 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 <i>PIK3CA</i>-related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-06-24
DOI
https://doi.org/10.1073/pnas.2424867122
Citations
2
Primary Topic
Nerve injury and regeneration
Type
article
Field-Weighted Citation Impact
1.82
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article

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

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2 citations
Proceedings of the National Academy of Sciences
Nerve injury and regeneration
1.82
article

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

Alessandra Bolino, Patrick Villarèse, Antoine Fraissenon, Charles Bayard, G Morin, Thomas Viel, Laurent Guibaud, Sanela Protic, Sophia Ladraa, Vahid Asnafi, Gwennhaël Autret, Nicolas Goudin, Geneviève Gourdon, Quitterie Venot, Roberta Di Guardo, Bertrand Tavitian, Clément Hoguin, Sato Magassa, Sophie Kaltenbach, Franck Mayeux, Marina Firpion, Sylvie Fraïtag, Estelle Balducci, Guillaume Canaud
article en
2 citations

Abstract

<i>PIK3CA</i>-related disorders are rare genetic disorders due to somatic gain-of-function mutations in <i>PIK3CA</i> during embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients with <i>PIK3CA</i>-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 <i>PIK3CA</i> gain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed that <i>PIK3CA</i>-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 <i>PIK3CA</i> 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 <i>PIK3CA</i>-related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.

Proceedings of the National Academy of SciencesVol. 122(26)
Hôpital Necker-Enfants Malades (FR), Vita-Salute San Raffaele University (IT), Inserm (FR), Université Paris Cité (FR), Sorbonne Université (FR), Hôpital Femme Mère Enfant (FR), Institut Necker Enfants Malades (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Nord (FR), Paris Cardiovascular Research Center (FR), IRCCS Ospedale San Raffaele (IT), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (FR), Centre de Recherche en Myologie
Good health and well-being
Openalex Percentile: Top 15%
Nerve injury and regeneration
1.82
DOIOpen Access PDFOpenAlex
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