Events

From Huntington Disease to neuronal transport: Vesicles have their on-board fueling and navigational systems to self-direct and detoxify the axon  

Short bio 

Frédéric Saudou, Professor of Cell Biology at Grenoble University and director of the GIN from 2013 to 2023 is a leader in the fields of neurobiology of Huntington’s disease and mechanisms of neurodegeneration. His research team “Intracellular Dynamics and Neurodegeneration” studies the role of the huntingtin protein in intracellular trafficking and how this function is perturbed in Huntington's disease with the ultimate goal of developing compounds of therapeutic interest. 

Abstract 

Huntington’s disease (HD) 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 associates to vesicles and acts a scaffold for the molecular motors and through this function, regulates the efficiency and directionality of vesicular transport in neurons. HTT controls the microtubule-based fast axonal transport (FAT) of neurotrophic factors such as BDNF. Importantly, polyQ expansion in HTT alters this function, leading to a decrease in neurotrophic support and death of striatal neurons.  

By developing microfluidic approaches allowing to study healthy and defective corticostriatal networks in vitro that are compatible with high-resolution videomicroscopy and the use of biosensors, we found that HTT scaffolds the whole glycolytic machinery on vesicles to supply constant energy, independently of mitochondria, for the transport of vesicles over long distances in axons. We also found that HTT by activating specific signaling complexes ensures that certain types of vesicles such as signaling endosomes find their way to the nucleus by having an on-board navigational system. Importantly, we found that HTT could orchestrate different energy supply pathways depending on the type of vesicles and the level of cellular stress. We will discuss how these machineries are activated in physiological situations and how they are altered in disease. 

For discussion slots with the speaker, contact Anu Wartiovaara  anu.wartiovaara@helsinki.fi 

For student & postdoc lunch, contact Yilin Kang,  Yilin.kang@helsinki.fi 

Welcome to this exciting seminar!  

Anu & Yilin 

Five recent publications 

1. Mc Cluskey M, Dubouchaud H, Nicot AS and Saudou F. A vesicular Warburg effect: Aerobic glycolysis occurs on axonal vesicles for local NAD+ recycling and transport. Traffic. 2023 Dec 12. doi: 10.1111/tra.12926. PMID: 38084815 

2. Vitet H, Bruyère J, Xu H, Séris C, Brocard J, Abada YS, Delatour B, Scaramuzzino C, Venance L and Saudou F. Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning. Elife. 2023 Jul 11;12:e81011. doi: 10.7554/eLife.81011. PMID: 37431882 

3. Scaramuzzino C, Cuoc EC, Pla P, Humbert S and Saudou F. Calcineurin and huntingtin form a calcium-sensing machinery that directs neurotrophic signals to the nucleus.Sci Adv. 2022 Sci Adv. 2022 Jan 7;8(1):eabj8812. doi: 10.1126/sciadv.abj8812. 

4. Virlogeux A, Scaramuzzino C, Lenoir S, Carpentier R, Louessard M, Genoux A, Lino P, Hinckelmann MV, Perrier AL, Humbert S and Saudou F. Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice. Sci Adv. 2021 Mar 31;7(14):eabb0799. doi: 10.1126/sciadv.abb0799. 

5. Bruyère J, Abada YS, Vitet HM, Fontaine G, Deloulme JC, Cës A, Denarier E, Pernet-Gallay K, Andrieux A, Humbert S, Potier MC, Delatour B and Saudou F. Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin, eLife, 2020 May 26;9:e56371. doi: 10.7554/eLife.56371.