Huntingtin and the control of long distance transport of synaptic / extrasynaptic signals in health and disease

• Applicant: Dr. Michael R. Kreutz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258728186

Huntingtin (HTT) the protein that when mutated causes Huntingtons 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. HTT interacts with the molecular motors dynein and kinesin to regulate the efficacy and the directionality of transport placing HTT at the center of functional nodes that regulate the transport of signals over long distances 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 microtubuli. Several studies have provided compelling evidence that huntingtin interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that huntingtin might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we will address this idea. We will also investigate whether perturbation of microtubule-based transport contributes to impairments in long-distance signalling in HD. More specifically we propose 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 assume 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 will test whether HTT and Jacob interact directly and we aim to determine the molecular identity of the signals transported to the nucleus in normal and HD conditions with special emphasis on non-vesicular transport of transcriptional regulators. Most important we want to assess whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. Taken together the proposed work program will shed new light on the physiological function of HTT, which has been neglected and at the same time we will learn how the investigated mechanisms impacts on the pathophysiology of the disease.

• DFG Programme: Research Grants
• International Connection: France
• Participating Person: Professor Dr. Frederic Saudou