Deciphering the translation machinery localized on motile TrkB endosomes in health and HD – TRAPHD

Neurotrophins (NTs) signaling is essential for neuronal survival and network maintenance. It is mediated by NT binding to its receptor and depends on the directed transport of signaling endosomes from the synapse to the nucleus (eg: BDNF-TrkB signaling endosomes in the corticostriatal circuit). Others and we have shown that the endosomal journey extends to postsynaptic sites located in the distal dendrites. Such long-range transport supports brain connectivity. Another important mechanism in the dendrites involves local translation (possibly associated with organelles).

Unmet scientific needs: What are the signals that instruct local translation and how do they transit from axon terminals to the distal dendrites? How the full machinery required for local translation is brought there? Are these signaling and translation mechanisms relevant in disease?

Novel Hypothesis: The huntingtin-Calcineurin (HTT-CaN) is a major mediator to direct BDNF-TrkB signaling endosomes from axon terminals to distal dendrites acting as autonomous local micro-platforms bearing all the elements to provide translation. Such machinery is defective in HD.

We will Aim1: decipher the contents of the HTT-CaN-TrkB signaling endosomes in terms of protein, mRNA, tRNA and metabolites and their responses to BDNF signal; Aim2: investigate the translation functionality of motile endosomes depending on their location and Aim3: identify the consequences of mHTT on TrkB endosomes function/dysfunction.

Impact: We will provide the ground breaking knowledge on the identity and function of key actors of brain connectivity and its alteration in HD. Feasibility: The combination of our unique expertise in state-of-the-art microfluidic devices to investigate circuits in HD brain-on-a-chips and in the investigation of the translation machinery at an unprecedent spatiotemporal resolution put our consortium in a unique position to fulfill this ambitious programme.