Aller au contenuAller au menuAller à la recherche

Frédéric SaudouHuntington's disease: Huntingtin and the control of cellular dynamics

Abstract :


Huntington’s disease (HD) is a fatal neurodegenerative disorder that affects 1 in 10000 individuals of European origin.
The neuropathology of HD involves neuronal dysfunction and the selective death of striatal neurons in the brain. The mutation that causes disease is an abnormal expansion of a polyglutamine (polyQ) stretch in the N-terminus of the 350 kD protein huntingtin. The mechanisms by which huntingtin induces dysfunction and death of neurons in the brain are not clearly understood but they involve in part the loss of the protective properties of wild-type huntingtin.
We previously reported that huntingtin is subjected to phosphorylations such as S421 by the IGF-1/Akt pathway that modify its toxicity, suggesting that protein context, and thereby huntingtin function is a crucial regulator of the toxicity elicited by the polyQ expansion. Indeed, huntingtin function is crucial for pathogenesis as we demonstrated that huntingtin controls the microtubule-based transport of neurotrophic factors such as BDNF. This function is altered in disease, leading to a decrease in neurotrophic support and death of striatal neurons.
We recently demonstrated that huntingtin phosphorylation at S421 by the IGF-1/Akt pathway restores huntingtin ability to transport vesicles along microtubules in HD. We also analyzed the function of this phosphorylation on wild type htt and found an unexpected role in transport directionality further demonstrating the important role of htt as a key regulator of axonal transport in health and disease. Here we will report a new function for huntingtin in the control of cellular dynamics process and how these processes are altered in normal and pathological conditions. We will also discuss how such mechanisms are regulated by phosphorylation thereby providing new therapeutic approaches in HD.

Selected publications

Elongator - an emerging role in neurological disorders.Nguyen L, Humbert S, Saudou F, Chariot A.Trends Mol Med. 2009 Dec 23. [Epub ahead of print]
Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease.Pineda JR, Pardo R, Zala D, Yu H, Humbert S, Saudou F.
Mol Brain. 2009 Oct 27;2(1):33.

Daniel Choquet