Descripción del proyecto
El papel de la proteína huntingtina para la salud y en la enfermedad de Huntington
La enfermedad de Huntington es un trastorno cerebral progresivo hereditario que se caracteriza por el descontrol del movimiento, la alteración de la cognición y trastornos psiquiátricos relacionados con la disfunción cerebral y no con una reacción del paciente al diagnóstico. Es causada por una mutación en el gen HTT que codifica la proteína huntingtina. La huntingtina se requiere para el transporte axonal rápido del factor neurotrófico derivado del cerebro (BDNF) y este transporte es necesario para el funcionamiento normal del cerebro. FUELING-TRANSPORT está investigando el papel de la actividad neuronal en la modulación del transporte rápido, además de las fuentes de energía del transporte, y en qué medida podrían verse afectadas por la mutación del gen HTT. Descubrir los vínculos entre la actividad neuronal, el metabolismo energético y el transporte del BDNF en el contexto del HTT podría ayudar a identificar múltiples dianas terapéuticas.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
38058 Grenoble
Francia