Revealing alternative splicing control of clathrin structural plasticity in health and disease - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2019

Revealing alternative splicing control of clathrin structural plasticity in health and disease

Résumé

Clathrin-mediated endocytosis is the best characterized process for the entry of proteins and lipids at the plasma membrane of eukaryotic cells. It is also the Achilles’ heel for human diseases such as neurodegenerative diseases and congenital myopathies. While neurons form small clathrin-coated pits for fast endocytosis at synapses, muscle cells form large flat clathrin-coated plaques for cell adhesion. Despite its vital importance, it remains unclear how this diversity is achieved. We discovered that the exclusion of single developmentally regulated exons in clathrin can switch the mechanism of clathrin polymerization. We show that alternative splicing of developmentally regulated exons within endocytosis proteins allows a switch from basal endocytosis to a fast endocytic activity in neurons and adhesion plaques in muscle. To visualize the types of structures associated with each isoform, we developed a correlative super resolution/metal-replica electron microscopy technique to localize clathrin and its partners at nanoscale resolution and engineered exon skipping constructs to manipulate alternative splicing of endocytosis proteins in neurons and myotubes. We used myotonic dystrophy type 1, a spliceopathy affecting motor and cognitive functions, as a model to decipher the effect of alternative splicing on endocytosis proteins in neurons and muscle, and drive exon inclusion strategies to rescue clathrin defects. We show that myotonic dystrophy patients present mis-regulated splicing of endocytosis proteins and that loss of a specific exon in clathrin alone is able to induce myotonia as well as muscle fragility associated with features of muscular dystrophy. This work advances our understanding on fundamental biology of endocytosis by demonstrating how new protein isoforms tailor clathrin polymerization in differentiated cells and provides the proof of concept that defective clathrin assemblies can be rescued in patient cells by restoring mis-regulated exons.
Fichier non déposé

Dates et versions

hal-04007054 , version 1 (27-02-2023)

Identifiants

  • HAL Id : hal-04007054 , version 1

Citer

Moulay Gilles, Lainé Jeanne, Lemaître Mégane, Bitoun Marc, Furling Denis, et al.. Revealing alternative splicing control of clathrin structural plasticity in health and disease. The physics and chemistry of endocytosis at multiple scales, EMBO, Sep 2019, Ischia, Italy. ⟨hal-04007054⟩
28 Consultations
0 Téléchargements

Partager

Gmail Mastodon Facebook X LinkedIn More