- Project Title: The role of tandem repeats in neurodegenerativediseases: a genomic and proteomic approach
Funding: MIUR - Italian Minsitry for Education, University and Research
Programme: PRIN 2015 Research Projects of National Relevance
Partners: CNR-IIT (Pisa), Università dell’Insubria , Università del Piemonte Orientale.
Project Coordinator: Prof. Sandra D’Alfonso (Università del Piemonte Orientale)
Duration: 3 years (2017-2019).
Funding (total): 325,000 Euro
AIM OF THE PROJECT:
Tandem repeats polymorphisms (TRPs) are a class of sequence variations showing a growing importance as causative or
susceptibility factors in neurodegenerative diseases. We will focus on Amyotrophic lateral sclerosis (ALS) and Spinocerebellar
ataxias (SCA) since TRPs expansions account for a large fraction of cases, making this class of variants good candidates to
explain the missing hereditability of these diseases. Parkinsonís syndromes (PS) will be also analysed because of its
association with TRPs causing ALS and SCA (i.e. c9orf72 and ATXN2). So far, TRPs were never systematically analyzed in
these diseases because they represent a remarkable challenge to current next generation sequencing (NGS).
The general aim of this study is to perform a systematic analysis of TRPs localized in all gene regions in the pathogenesis of
ALS, SCA and PS by combining NGS and novel bioinformatics tools. A genomic and proteomic characterization of patients
carrying different known and novel disease-associated TRPs will be also performed.
to identify novel TRPs involved in the pathogenesis of neurodegenerative diseases through a genome-wide
screen. TRPs will be analysed in whole genome sequencing (WGS) data of ALS , SCA , PS patients and
controls. Results will be replicated in independent cohorts ( ALS, SCA, PS and controls). A proteomic
signature associated to the novel disease-associated TRPs will be performed by shotgun proteomics on patient fibroblasts.
to identify genomic and proteomic signatures contributing to the different disease phenotypes associated to known TRP
expansions (c9orf72 and ATXN2).We will compare the sequence and methylation profile of the c9orf72 region in individuals
with different clinical phenotypes (ALS vs Frontotemporal dementia) stratified for c9orf72 expansions.The length and purity
of ATXN2 CAG repeat will be characterized in ALS, SCA and PS patients.
Fibroblasts of c9orf72 and ATXN2 expansion carriers showing different disease phenotypes will be analysed by shotgun
proteomics. A systems biology analysis of genomic and protein signatures in c9orf72 and ataxin2 expansion carriers showing
different phenotypes will be performed.
The study design will allow to detect novel disease-associated TRPs with frequencies >/= than TRPs already identified, with a
Moreover, we will provide new insight in the pathogenic mechanism associated with these neurodegenerative diseases of
known or novel TRPs
Last update: November 14th, 2016
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