Research project

RF 2019 12370224 (DSB.AD004.350)

Thematic area

Biomedical sciences

Project area

Neuroscienze (DSB.AD004)

Structure responsible for the research project

Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB)

Project manager

ANTONIO SIMEONE
Phone number: 0816132401
Email: antonio.simeone@igb.cnr.it

Abstract

Parkinson's disease (PD) represents one of the most frequent neurodegenerative disorders whose socio-economic impact
is enormous. Although its genetic diagnosis is still challenging, we recently identified 169 disrupting variants in 26 candidate
genes for late onset PD (LOPD), 16 of them never associated to PD before. We demonstrated that the co-inheritance of
multiple rare variants (>2) in these 26 genes predicts LOPD risk in about 20% of individuals with >95% of specificity. Here
we propose to: i) consolidate the diagnostic protocol by extending the NGS studies to a huge number of PD cases and
controls; ii) examine the effect of single or combined variants on phenotypic manifestation of PD (motor and cognitive signs
as well as age at onset, neuroimaging changes and dyskinesia); and iii) generate mouse models humanized for PD
promising mutations to provide unique tools for the study of dopaminergic (DA) neurodegeneration and the development of
precise pharmacological approaches.

Goals

The project intends to assess the polygenic burden of rare disruptive mutations in PD and how they influence the
phenotype/pathological heterogeneity of disease. The study is based on the hypothesis that the co-inheritance of multiple
rare variants in Mendelian genes may increase the risk of some diseases, including PD, in a non-Mendelian fashion and
that this may influence clinical signs as well as progression, and prognosis of the disease. The project will contribute
expanding the knowledge of the genetic architecture of PD taking advantage of genetic characterization of the study sample
and may be relevant to genetic testing and counselling of patients with PD and their families. Moreover, the realization of
mouse models of PD, carrying single or multiple mutations, may be important for a better understanding of the mechanism
underlying the pathology and paving the way for new therapeutic strategies.

Start date of activity

17/05/2021

Keywords

Gene discovery and functional analysis using animal and cellular (human and animal) models:, Diagnostic tool for Parkinson's Disease, Mouse modeling and phenotype analysis

Last update: 19/07/2024