Description du projet
Démêler le rôle de la protéine huntingtine dans la santé et dans la maladie de Huntington
La maladie de Huntington est un trouble cérébral progressif héréditaire caractérisé par des mouvements incontrôlés, des troubles cognitifs et des troubles psychiatriques liés à un dysfonctionnement cérébral et non à la réaction d’un patient au diagnostic. Elle est causée par une mutation du gène HTT qui code la protéine huntingtine. La huntingtine est nécessaire pour le transport axonal rapide du facteur neurotrophique dérivé du cerveau (BDNF). Ce transport est nécessaire au fonctionnement normal du cerveau. FUELING-TRANSPORT étudie le rôle de l’activité neuronale dans la modulation du transport rapide ainsi que les sources d’énergie pour le transport, et comment la mutation HTT pourrait les affecter. L’élucidation des liens entre l’activité neuronale, le métabolisme énergétique et le transport du BDNF dans le contexte du HTT pourrait pointer vers de multiples cibles pour les thérapies.
Objectif
Fast axonal transport (FAT) of brain-derived neurotrophic factor (BDNF) is essential for brain function. It depends on huntingtin (HTT), the protein that when mutated causes Huntington’s disease (HD), a devastating and still incurable disorder. Unmet scientific needs: BDNF is regulated by neuronal activity and its transport requires energy. Yet we do not know if FAT of BDNF is regulated by neuronal activity and if HTT facilitates activity-dependent transport. The energy sources for FAT of BDNF and their regulation by activity remain unclear, as do the exact mechanisms of BDNF transport reduction in the HD-causing mutation. Novel hypothesis: HTT plays a key role in channeling energy by coupling energy production by glycolytic enzymes on vesicles to consumption by molecular motors for efficient axonal transport. This function is altered in HD and plays a crucial role in disease progression. By providing energy directly to vesicles, we can restore transport and slow down neurodegeneration in HD. Aim 1: investigate energy sources for axonal transport and their regulation by HTT upon high neuronal activity. Aim 2: investigate how pathogenic mutation in HTT affects response to neuronal activity and vesicles capacity to produce energy. Aim 3: restore energy sources in HD to rescue axonal transport and slow down neurodegeneration. Impact. This work will advance the understanding on how electrical activity essential for brain function regulates energy metabolism to fuel transport, specifically transport of BDNF. We will reveal essential new knowledge on the HTT function and dysfunction. This will likely lead to novel therapeutic strategies for HD. Feasibility: we have expertise in developing innovative microfluidic circuits for studying axonal transport in reconstituted neuronal circuits and in identifying new metabolic and signaling pathways. This, together with my expertise on HTT biology, puts my lab in a unique position to fulfill this ambitious programme.
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ERC-ADG - Advanced GrantInstitution d’accueil
38058 Grenoble
France