The Department of Biomedicine

BBB seminar: Frédéric Saudou

Huntington's disease: from axonal transport to neurotrophin signaling and energy homeostasis

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Frédéric Saudou
Grenoble Institute of Neurosciences, University Grenoble Alpes and INSERM Research Center U1216, Grenoble and Grenoble University Hospital CHUGA, France

Huntington’s disease is caused by the abnormal polyglutamine (polyQ) expansion in the N-terminal part of huntingtin (HTT), a large protein of 350kDa. Over the past years, we have proposed that HTT acts as a scaffold for the molecular motors and through this function, regulates the efficiency and directionality of vesicular transport along microtubules in neurons. This function is conserved in Drosophila. In particular, HTT controls the microtubule-based fast axonal transport (FAT) of neurotrophic factors such as BDNF. HTT function in transport is modulated by direct phosphorylation/dephosphorylation via specific signaling pathways. Importantly, polyQ expansion in HTT alters this function, leading to a decrease in neurotrophic support and death of striatal neurons. The defect in transport might not be restricted to axons but could also involve defects in the retrograde transport of TrkB, the BDNF receptor, in striatal dendrites.

In addition to the role of HTT in scaffolding the molecular motors both in cortical and striatal neurons, we found that HTT scaffolds GAPDH on vesicles and that vesicular GAPDH is necessary to propel vesicles in GAPDH deficient neurons. Here we will extend these findings and discuss how HTT by specifically localizing the glycolytic machinery on vesicles may supply constant energy for the transport of vesicles over long distances in axons.

We will also discuss how this machinery is altered in a disease situation using new approaches that allow the study of defective networks in vitro through the development of microfluidic systems compatible with high-resolution videomicroscopy and the use of biosensors to reconstitute and identify each component of the corticostriatal network.

Chairperson: Clive Bramham, Department of Biomedicine