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Die Rolle von Huntingtin bei nicht-vesikulären Transport von Proteinen aus der Synapse zum Zellkern

Fachliche Zuordnung Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Förderung Förderung von 2014 bis 2019
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 258728186
 
Erstellungsjahr 2020

Zusammenfassung der Projektergebnisse

Huntingtin (HTT) the protein that when mutated causes Huntington’s disease (HD), a devastating neurological disorder, acts as a scaffold for protein complexes with an emerging role in the transport of vesicles and proteins in axons and dendrites. At an early stage of the disease no structural damage exists but rather an impairment of synaptic function that manifests in a shift from synaptic to extrasynaptic N-Methyl-D-Aspartate-receptor (NMDAR) signalling. Jacob is a synapto-nuclear protein messenger that encodes and transduces the synaptic or extra-synaptic origin of NMDAR signals to the nucleus and that plays a role in regulation of gene expression either leading to cell death or promoting cell survival and synaptic plasticity. Nuclear trafficking of Jacob requires an active importin- and dynein-mediated retrograde transport along microtubules. Several studies have provided compelling evidence that HTT interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that HTT might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we wanted to address the idea that HTT and Jacob could play a major role in integrating long-range signals from the synapse to the nucleus and consequently will modify gene expression in health and in HD. We assumed that a functional interplay between Jacob, a protein that can dock an NMDAR-derived signalosome to nuclear target sites and mutant HTT might contribute to neurodegeneration in HD. We wanted to test whether HTT and Jacob interact directly and we aimed to determine whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. The work was funded by a ANR/DFG collaboration grant. The collaboration involved the lab of Prof. Frederic Saudou at the Grenoble Institute of Neuroscience (GIN).

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