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Project

Exploring the role of DPP6 loss and hyperexcitability in neurodegenerative brain diseases.

Using advanced genetic and genomic studies, as well as expression studies in brain tissue of patients and electrophysiological modelling in Xenopus laevis oocytes, we identified dipeptidyl peptidase 6 (DPP6) as novel candidate gene in neurodegenerative brain diseases (NBD) (Cacace et al., Journal of Neurochemistry (2016) 138:231-232 and Cacace et al., under revision). Our results suggested a loss-of-function mechanism leading to the dysregulation of the normal DPP6 function in relation to its molecular partner, the potassium channel Kv4.2. In this project proposal, we plan the follow-up of our genetic findings. We hypothesize that loss of DPP6 could be crucial in alteration of brain network activity and consequentially neuronal hyperexcitability and neurodegeneration. We aim to disentangle this hypothesis using in-vitro studies in both patients' brain tissue and in cellular models, as well as in vivo studies to establish the validity of the DPP6 KO mouse model in NBD. This project aims to understand the entity of pathological consequences of DPP6/Kv4.2 dysregulation in relation to NBDs. The project outcomes will represent a fundamental milestone for novel assumptions on disease mechanism(s). Our final goal is to develop an in-vitro assay for compound testing, with a (long-term) translational application such as the development of (more personalized) preventive/efficacious therapeutic interventions.
Date:1 Oct 2017 →  30 Sep 2020
Keywords:NEURODEGENERATIVE DISEASES
Disciplines:Genetics, Systems biology, Molecular and cell biology
Project type:Collaboration project