Frédéric Saudou
Host institution: University Grenoble Alpes
Laboratory: GIN
Call for Projects: Advanced (LS5)
Project name: FUELING-TRANSPORT – Deciphering the Role of Huntingtin in Energy Supply for Axonal Transport in Health and Huntington’s Disease
Amount: 2.36 M€
Description:
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.