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Project

Characterization of HINT1 knockout Drosophila model for peripheral neuropathy.

Recessive loss-of-function mutations in HINT1 rank among the leading causes of axonal peripheral neuropathy (Charcot-Marie-Tooth disease, CMT). They are associated with a severe, progressive and early-onset phenotype for which no curative treatment exists to date. HINT1 is a pleiotropic and evolutionary conserved purine phosphoramidase with unknown endogenous substrate(s) and its role in the peripheral nervous system is utterly unexplored. The overall aim of my postdoctoral project is to elucidate the pathomechanisms underlying HINT1-related neurodegeneration and create therapeutic opportunities for peripheral neuropathies. Building on promising preliminary data and the expertise available in our research group, I will establish and characterize the first in vivo models of HINT1 neuropathy using Drosophila as a surrogate system. Flies deficient for the HINT1 orthologue or expressing either human wild type or CMT-causing HINT1 alleles will be thoroughly investigated for morphological and behavioral signs of neurodegeneration at different developmental stages and in assays relevant to the CMT pathology in humans. This in-depth analysis will provide mechanistic insights into the (mal)functioning of HINT1 in the peripheral nervous system and can lead the way towards therapeutic intervention.
Date:1 Apr 2019 →  30 Mar 2020
Keywords:MOLECULAR NEUROPATHOLOGY, DROSOPHILA MELANOGASTER, CHARCOT-MARIE-TOOTH DISEASE, HEREDITARY NEUROPATHIES
Disciplines:Neurological and neuromuscular diseases