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Project

Investigating the role of DPP6 in neurodegenerative dementia: an hypothesis based approach.

Advanced genetic and genomic studies as well as expression studies in brain tissue of patients and electrophysiological modelling in Xenopus laevis oocytes, performed by our research group, identified DPP6 as novel candidate gene associated with frontotemporal dementia (FTD) (Cacace et al., under revision). Our results suggested a possible loss-of-function mechanism, leading to synaptic hyperexcitability due to dysregulation of the normal DPP6 function in relation to its molecular partner, the potassium channel Kv4.2. Based on our previous data as well as literature information, we hypothesize that DPP6 might be a crucial protein in brain neurodegeneration. In this project proposal, we aim to disentangle this hypothesis by pursuing it from different angles. We aim to investigate the brain expression of both DPP6 and Kv4.2 in additional dementia patients, independently of their genetic cause. We will investigate if a direct interaction between DPP6 and other known dementia proteins exist. Moreover, we will perform in-vitro studies to detect mutation-specific characteristics by protein stability and localization assays. In order to frame our data in a comprehensive picture, we will perform a pilot study using a Dpp6-KO mouse model in which we will evaluate whether a specific pattern of alteration in the protein orthologues of the known dementia genes is present. This project proposal and its outcome will represent a fundamental milestone to understand how extensive the DPP6/Kv4.2 dysregulation in neurodegenerative brain diseases (NBD) can be. The resulting knowledge will allow novel speculations on disease mechanism(s) and will trigger novel projects and long-term research.
Date:1 Apr 2017 →  31 Mar 2018
Keywords:POTASSIUM CHANNEL, DPP6, NEURODEGENERATIVE DEMENTIA
Disciplines:Systems biology