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

Proc Natl Acad Sci U S A. 2025 Jul;122(26):e2424867122. doi: 10.1073/pnas.2424867122.

Quitterie Venot ^# ¹ ² ³, Marina Firpion ^# ¹ ² ³, Sophia Ladraa ^# ¹ ² ³, Charles Bayard ¹ ² ³, Sato Magassa ¹ ², Roberta Di Guardo ⁴, Antoine Fraissenon ¹ ² ⁵ ⁶ ⁷, Clément Hoguin ¹ ² ³, Sanela Protic ¹ ² ³, Gabriel Morin ¹ ² ³, Franck Mayeux ¹ ² ³, Genevieve Gourdon ⁸, Sylvie Fraitag ⁹, Estelle Balducci ¹ ² ¹⁰, Sophie Kaltenbach ¹ ² ¹⁰, Patrick Villarese ¹ ² ¹⁰, Vahid Asnafi ¹ ² ¹⁰, Thomas Viel ¹¹, Gwennhael Autret ¹¹, Bertrand Tavitian ¹ ¹¹, Nicolas Goudin ¹², Laurent Guibaud ² ⁷, Alessandra Bolino ^# ⁴ ¹³, Guillaume Canaud ^# ¹ ² ³

Affiliations

1 Université Paris Cité, Paris 75015, France.
2 INSERM U1151, Institut Necker-Enfants Malades, Paris 75015, France.
3 Unité de Médecine Translationnelle et Thérapies Ciblées, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris 75015, France.
4 Division of Neuroscience, Human Inherited Neuropathies Unit, Institute of Experimental Neurology, Ospedale San Raffaele, Milan 20132, Italy.
5 Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, Hospices Civiles de Lyon, Bron 69500, France.
6 Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé UMR 5220, Villeurbanne 69100, France.
7 Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne 42270, France.
8 Sorbonne Université, Inserm, Centre de Recherche en Myologie, Paris 75013, France.
9 Laboratoire d'Anatomie Pathologique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris 75015, France.
10 Laboratoire d'Oncohématologie, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris 75015, France.
11 Plateforme Imageries du Vivant, Université de Paris, Paris Centre de Recherche Cardiovasculaire, INSERM, Paris 75015, France.
12 Necker Bio-Image Analysis, INSERM US24/CNRS UMS 3633, Paris 75015, France.
13 Vita-Salute San Raffaele University, Milan 20132, Italy.
# Contributed equally.

PMID: 40553493 DOI: 10.1073/pnas.2424867122

Abstract

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.

Keywords

PIK3CA; nerve anomalies; somatic mutation.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-15244

Alpelisib

99.95%, PI3Kα Inhibitor

PI3K

Cancer

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