The second Dementia Consortium has been set up in 2018, which has so far developed and launched four new target-based projects.
Validating TTBK1 as a target for AD: TTBK1 knock-down and small molecule inhibitor approaches
Prof Tsuneya Ikezu, Boston University
The aim of this project is to demonstrate that supressing TTBK1 could prevent progression of AD through suppression of pTau accumulation and associated neuroinflammation.
The accumulation of hyper-phosphorylated microtubule-associated protein tau (pTau) first appears in the entorhinal cortex (EC) layer II in the prodromal stage of Alzheimer’s disease and propagates to the hippocampal field and temporal neocortex at the early onset of AD.
CLPP-dependent activation of mitochondria quality control signalling in neurodegenerative diseases
Dr Nicoleta Moisoi, De Montfort University
The aim of this project is to test the hypothesis that activating the mitochondrial peptidase CLPP, enhances mitochondrial quality control signalling which has a neuroprotective action in invitro and invivo models of Parkinson’s disease.
Preliminary evidence shows that genetic and pharmacologic activation of CLPP initiates a cascade of signalling mechanisms that project against mitochondrial dysfunction in models in PD. Activation may also be neuroprotective in Alzheimer’s disease.
ER-mitochondria signalling as a new target for Dementia (VAPB-PTPIP51 tethering)
Prof Chris Miller, King’s College London
The aim of this project is to confirm the hypothesis that damage to the endoplasmic reticulum (ER) mitochondria signalling via loss of the interaction between the VABP and PTPIP51 (ER-mitochondrial tethers), is a driver of early pathology in FTD/ALS with relevance also to Alzheimer’s disease and Parkinson’s disease.
Identification of tool compounds targeting the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts
Dr Tennore Ramesh & Guillaume Hautbergue, University of Sheffield
The aim of the project is to demonstrate that inhibiting the interaction between SRSF1 and C9orf72 prevents the build up of pathogenic dipeptide repeat proteins in FTD/ALS. C9orf72 genetic mutations cause the majority of familial and sporadic ALS and FTD. Subsequent nuclear export of expanded C9orf72 RNA via SRSF1, results in generation of toxic di-peptide repeat proteins.