Rôle de la huntingtine dans le muscle

Abstract : Huntington Disease (HD) is a rare multisystemic neurodegenerative genetic disorder, which combines psychiatric, cognitive and motor alterations. It is caused by an increase in CAG repeats in the huntingtin gene, resulting in an expansion of polyglutamine stretch in the protein. This induced a loss of the huntingtin protein (HTT) normal function associated with production of a mutant protein. HTT is an ubiquitous microtubules associated protein, with numerous functions among which vesicles and organelles traffic along microtubules. Along this line, one of its functions could be the traffic of reticulum vesicles to form contact point with the plasma membrane in neurons. Moreover, a phenocopy named Huntington’s disease like 2 is due to junctophilin-3 loss of function. Junctophilin 3 is involved in contact points between endoplasmic reticulum and plasma membrane in neurons. These studies are dedicated to the validation of the hypothesis of the role of HTT in contact points between endoplasmic reticulum and plasma membrane in another model, in which contacts between reticulum and plasma membrane are of major importance: the skeletal muscle cell. Indeed, the contact points between sarcoplasmic reticulum and plasma membrane (T-Tubule), called the triads, are the basis of excitation-contraction coupling in muscle. In these studies, we develop cellular and animals models with a loss of expression of HTT in skeletal muscle specifically. Theses studies show that calcium release is altered at the cellular level and muscle force is altered at animal model level. Theses alterations are correlated with loss of expression of the main receptors of the triad. Finally, fragment of the normal protein can restore calcium defects. Theses studies put forward the role of huntingtine in skeletal muscle.
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Brice Poreau. Rôle de la huntingtine dans le muscle. Neurosciences [q-bio.NC]. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV077⟩. ⟨tel-02314260⟩

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