Team Name: ‘Team "Intracellular Dynamics and Neurodegeneration"’

Link to team page: https://neurosciences.ujf-grenoble.fr/search/team-saudou-intracellular-dynamics-neurodegeneration?language=en

Institute: Grenoble Institute of Neuroscience, Inserm U1216 & Université Grenoble Alpes

Address: Bat EJ Safra, Chemin Fortuné Ferrini, 38042 Grenoble

Description of research

Huntington’s disease is characterized by the selective death of striatal and cortical neurons in the brain. The mechanisms by which mutant huntingtin (HTT) causes neurodegeneration remain elusive. Over the last years, we have proposed a major role of HTT in the regulation of fast axonal transport (FAT). We found that HTT regulates efficacy and the directionality of FAT through phosphorylation and that this phosphorylation restores FAT in disease situation (Cell 2004, EMBOJ 2008, HMG 2008). The role of HTT is not restricted to vesicles in axons as HTT by regulating intracellular trafficking regulates ciliogenesis (JCI 2011) and trafficking of TrkB endosomes in striatal dendrites (JNEUROSCI 2013). By investigating the role of HTT in FAT, we unraveled a fundamental role of the glycolytic enzymes GAPDH and PGK as the on-board provider of energy for the FAT. This function is controlled by HTT (CELL 2013). Together these studies highlight a fundamental role of HTT in intracellular trafficking and open new avenues not only for the study of neurodegenerative disorders but also for fundamental cell biology.

We want to better understand: how control of FAT efficiency and/or directionality by HTT impacts on neuronal activity and transmission; How HTT dysfunction in FAT regulates neurodegeneration in HD but also in other neurodegenerative disorders such as Alzheimer’s disease; We want to understand the consequences of specific cleavages on HTT function and neurodegeneration in health and disease; We are actively developing new physiologically relevant systems and/or tools to allow functional screening; Finally, we are putting efforts in translational research by close collaborations with HD clinicians. The achievement of these goals should lead to the development of novel therapeutic strategies for this devastating neurodegenerative disorder but might also reveal new regulatory mechanisms that are important well beyond the field of HD.

Research to be done in the context of Circprot

Based on the knowledge and expertise of the consortium in BDNF-TrkB signaling in health and Huntington’s disease and in stem cell research, we will investigate using microfluidic approaches the intracellular dynamics of BDNF and TrkB moelcules as well as their signaling in neuronal networks that reconstitute cortico-striatal connections. In particular we aim to reconstitute connections using neurons differentiated from iPSC. The next step will be to reconstitute neurons derived from HD mutant iPSC. We hope to understand better the contribution of both compartments (cortex and striatum) to the deficits observed in the cortico-striatal connection. The final objective is to identify pathways and/or drugs that are able to counteract such defects and that could have therapeutic interest.

 

 

Key publications

Hinckelmann MV, Virlogeux A, Niehage C, Poujol C, Choquet D, Hoflack B, Zala D, Saudou F. (2016) Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. Nat Commun. 7:13233. doi: 10.1038/ncomms13233.

El-Daher MT, Hangen E, Bruyère J, Poizat G, Al-Ramahi I, Pardo R, NiBourg N, Souquere S, Mayet C, Pierron G, Lévêque-Fort S, Botas J, Humbert S, Saudou F (2015) Huntingtin proteolysis causes toxicity through dynamin 1 dysregulation EMBO J. 34 , 2255-71.

Zala D, Hinckelmann MV, Yu H, Cunha M, Liot G, Cordelieres FP, Marco S and Saudou F (2013) Vesicular glycolysis provides on-board energy for axonal transport. Cell. 152, 479-91.

, Top30 of all time F1000 rec. See highlights in Nat Rev Neurosci, 2013, 14, 156-157; News & Views in Nature, 2013, 495,178-180.

Liot G, Zala D. Pla P, Mottet G, Piel M and Saudou F (2013) Mutant huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J Neuroscience 33, 6298-6309.

Keryer G, Pineda JR, Liot G, Jinho Kim J, Dietrich P, Benstaali C, Smith K, Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I and Saudou F. (2011) Ciliogenesis is Regulated by the Huntingtin-HAP1-PCM1 Pathway and is Altered in Huntington Disease. J. Clin Invest.,121, 4372-4382.