• 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. Parkinson’s 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.
• SPECIFIC AIMS:
  • 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 power >80%. Moreover, we will provide new insight in the pathogenic mechanism associated with these neurodegenerative diseases of known or novel TRPs

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Last update: November 14th, 2016
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