PROTECTMOVE

Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort

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Genes causative for recessively inherited Parkinson’s disease (PD) include Parkin and PINK1; rare homozygous mutations in these genes result in definite symptom expression. On the other hand, heterozygous mutations – a relatively common occurrence – may predispose to PD in a dominant manner with highly reduced penetrance. The largest described pedigree of Parkin mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of Parkin mutations who develop overt symptoms of Parkinson’s disease (PD), while others may have prodromal, or no obvious symptoms. In this project, we aim to dissect out the factors that modify the penetrance of these variants, using additional Parkin mutation carriers identified in the Cooperative Health Research in South Tyrol (CHRIS) study (comprising n=13,490 individuals from the same geographical region). By testing whether factors that influence mitochondrial function can alter penetrance of nuclear mutations, we observed an increased burden of heteroplasmic mtDNA mutations in affected vs. unaffected heterozygous Parkin and PINK1 (Phosphatase and tensin homolog-induced putative kinase 1) mutation carriers, which might explain the phenotypic (clinical, sub-clinical) discordance in these individuals with similar nuclear genetic background. However, the specificity of mtDNA variation and additional factors as penetrance markers and the molecular pathways involved ultimately leading to neurodegeneration, require further investigation with larger datasets. Within the DFG funded project ProtectMove, we are examining these questions. In 2020 DFG funding was renewed for further three years.

Publications
Generation and characterization of induced pluripotent stem cell (iPSC) lines of two asymptomatic individuals carrying a heterozygous exon 7 deletion in Parkin (PRKN) and two non-carriers from the same family
Castelo Rueda MP, Gilmozzi V, Riekschnitz DA, Di Segni M, Silipigni R, Pramstaller PP, Hicks AA, Pichler I, Zanon A (2022)
Journal article
Stem Cell Research
The impact of instruments selection on Mendelian Randomization results: a case study
Bottigliengo D, Caliebe A, König IR, Del Greco MF (2021)
Conference proceedings article

Conference: 42nd Annual Conference of the International Society for Clinical Biostatistics (ISCB42) Conference | Lyon | 18.7.2021 - 22.9.2021

More information: http://www.iscb2021.info/en

Molecular investigation of apparently healthy heterozygous Parkin mutation carriers
Castelo-Rueda MP, Zanon A, Gilmozzi V, Klein C, Pramstaller PP, Hicks AA, Pichler I (2021)
Presentation/Speech

Conference: 22nd International Congress of Parkinson's Disease and Movement Disorders International Congress of Parkinson's Disease and Movement Disorders | virtual | 17.9.2021 - 21.9.2021

Investigating the causal role of Inflammation on Parkinson's disease by a bidirectional Mendelian Randomization Approach
Bottigliengo D, Foco L, Seibler P, Klein C, König IR, Del Greco MF (2021)
Conference proceedings article

Conference: XI Congresso Nazionale SISMEC | Bari | 15.9.2021 - 18.9.2021

Frequency of Heterozygous Parkin (PRKN) Variants and Penetrance of Parkinson's Disease Risk Markers in the Population-Based CHRIS Cohort
Castelo Rueda MP, Raftopoulou A, Gögele M, Borsche M, Emmert D, Fuchsberger C, Hantikainen EM, Vukovic V, Klein C, Pramstaller PP, Pichler I, Hicks AA (2021)
Journal article
Frontiers in Neurology

More information: https://doi.org/10.3389/fneur.2021.706145

https://doi.org/10.3389/fneur.2021.706145

https://hdl.handle.net/10863/18802

Investigating the causal role of Inflammation on Parkinson's disease by a bidirectional Mendelian Randomization Approach
Bottigliengo D, Foco L, Seibler P, Klein C, König IR, Del Greco M F (2021)
Conference proceedings article

Conference: 2021 IGES Annual Meeting | | 13.10.2021 - 16.9.2021

More information: https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22431

https://doi.org/10.1002/gepi.22431

https://hdl.handle.net/10863/20573

The role of mitochondria in modifying penetrance of Parkin gene variants
Castelo MP, Trinh J, Zanon A, Rainer J, Bauer P, Kandaswamy KK, Werber M, Rolfs A, Grunewald A, Borsche M, Lohmann K, Klein C, Pramstaller PP, Pichler I, Hicks A (2019)
Presentation/Speech

Conference: International Congress of Parkinson's Disease and Movement Disorders | Nice | 22.9.2019 - 26.9.2019

https://hdl.handle.net/10863/12975

Our partners

University of Lübeck, Institute of Neurogenetics

University of Luxembourg, Luxembourg Centre for Systems Biomedicine

Project Team
1 - 6

Projects

1 - 3
Project

EPICIR

Epigenetics of Immunity in Cancer

Duration: September 2019 - July 2022Funding: Italy-Austria 2014-2020 (EUTC / EU ...

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