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Scientific abstract of the project

The deposition of intra- and extracellular protein deposits is a feature common to many neurodegenerative

diseases (NDs). Alzheimer’s disease (AD), Parkinson’s disease (PD)/Lewy body dementia (LBD), and

Spinocerebellar Ataxia type 3 (SCA3) are part of this group of diseases. We hypothesize that there exist

genes that when altered in sequence or expression increase the risk of developing any type of ND or modify

their age at onset (AAO). Such genes may play a key role in the development of many of the idiopathic forms

of these diseases and, thereby, be as relevant for NDs as p53 is for cancer. Our primary aim is to identify

generic modifiers of NDs by performing comprehensive bioinformatics analyses of modifiers identified

previously in targeted human and rodent studies, including high confidence genome-wide association studies

(GWAS), as well as in genetic screens in lower organisms such as yeast or Drosophila. In addition,

integration of the data from previous screens with proteomic and genomic information in disease-network

models will then identify possible novel generic modifiers. Predicted generic modifiers will be validated first

with the help of the analysis of expression profiles and RNAseq data. Selected modifiers will then be further

validated and characterized in vitro in mammalian cell models of AD, PD and SCA3. Finally, we will confirm

the effect of a few top-ranked modifiers, for which mechanistic studies have provided evidence of their mode

of action, in neurons derived from induced pluripotent stem cells (iPSCs), in transgene disease rodent

models and investigate whether the product of these modifier genes display significant alterations in human

brain tissue of autopsy-confirmed AD, PD, and SCA3 patients.

As generic modifiers and the components of the pathways that they affect will point to potential therapeutic

targets for a wide range of degenerative diseases,the results of this research will allow prioritisation of

targets for future drug screens and genomic studies.

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