Frédéric Saudou Leader of the Intracellular Dynamics and Neurodegeneration Team, Institut des Neurosciences, Grenoble, FranceFrédéric SaudouLeader of the Intracellular Dynamics and Neurodegeneration Team, Institut des Neurosciences, Grenoble, France
- 21 Jan 2022
- 11 h 30 min - 12 h 30 min
- Neuroscience Seminar Series
Huntingtin: Linking fast axonal transport, energy supply and neurotrophin signaling to neurodegeneratio, by Frédéric Saudou
Summary Huntingtin: Linking fast axonal transport, energy supply and neurotrophin signaling to neurodegeneration
Huntington’s disease is caused by the abnormal polyglutamine expansion in the N-ter part of huntingtin (HTT), a large protein of 350kDa. Over the past years, we proposed that HTT acts a scaffold for the molecular motors and through this function, regulates the efficiency and directionality of vesicular transport along microtubules in neurons. 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 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 disease situation using new approaches that allow the study of healthy and 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. Using these approaches, we recently identified compounds of therapeutic interest as well as new cellular mechanisms by which signaling endosomes find their way to the nucleus by having an on-board navigational system.
Frédéric Saudou, Professor at the University of Grenoble Alpes (UGA) and Hopital Practitioner at the Grenoble Alpes University Hospital (CHUGA), leads the research team “intracellular dynamics and neurodegeneration” that studies the role of the huntingtin protein in intracellular trafficking and how this function is perturbed in Huntington’s disease.
After a thesis under the supervision of René Hen (LGME, Strasbourg) on the cloning and invalidation of serotonin receptors in mice and flies, F. Saudou did a first postdoctoral fellowship in human genetics with Jean-Louis Mandel (IGBMC, Strasbourg) where he cloned the gene responsible for spinocerebellar ataxia type 2. He then performed a second postdoctoral fellowship with Michael Greenberg (Harvard Medical School, Boston) where he developed the first neuronal model of Huntington disease. Recruited at Inserm, he started his team in 2000 at the Institut Curie and discovered a role for huntingtin in the intracellular transport of neurotrophic factors and how this transport is altered in the disease.
Since 2014, F. Saudou is PU-PH UGA/CHUGA and director of the Grenoble Institut Neuroscience where he has developed microfluidic approaches to reconstitute neuronal circuits on chips and study their alteration in the disease. Through these approaches, he has shown a central role of huntingtin in the control of transport directionality in axons and their involvement in neuronal survival. In parallel, F. Saudou has shown that vesicles have their own energy machinery, glycolysis, on board, which allows them to self-propel inside neurons. One of the team’s priorities is to understand the alterations of these energetic processes in Huntington’s disease with the ultimate goal of developing compounds of therapeutic interest. Website :https://urlz.fr/h8gt and on twitter: @SaudouLab
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