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 (PRKN) and PINK1; rare homozygous mutations in these genes result in definite symptom expression. On the other hand, evidence suggests that heterozygous mutations – a relatively common occurrence – may predispose to PD in a dominant manner with highly reduced penetrance. The largest described pedigree of PRKN mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of PRKN 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 PRKN 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 PRKN and PINK1 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 to answer these questions. In 2020 DFG funding was renewed until 2024.

Publications
Deep mitochondrial genotyping in advanced cellular models of Parkinson’s disease indicates altered mitochondrial quality control mechanisms
Gilmozzi V, Lang M, Pramstaller PP, Pichler I (2023)
Presentation/Speech

Conference: MitoPorto | Porto | 12.5.2023 - 13.5.2023

Deep mitochondrial genotyping reveals altered mitochondrial quality control mechanisms in advanced cellular models of Parkinson’s disease
Lang M, Gilmozzi V, Pramstaller PP, Pichler I (2023)
Presentation/Speech

Conference: EUROMIT 2023 - International meeting on mitochondrial pathology | Bologna | 11.6.2023 - 15.6.2023

More information: https://euromit2023.eu/

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers
Castelo Rueda MP, Zanon A, Gilmozzi V, Lavdas AA, Raftopoulou AA, Delcambre S, Del Greco M F, Klein C, Grünewald A, Pramstaller PP, Hicks AA, Pichler I (2023)
Journal article
npj Parkinson's Disease

https://doi.org/10.1038/s41531-023-00499-9

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
A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease
Bottigliengo D, Foco L, Seibler P, Klein C, König IR, Del Greco M F
(2022)
Journal article
Brain

https://doi.org/10.1093/brain/awac193

Systematic review of Mendelian randomization studies on Parkinson’s disease
Kappen S, Bottigliengo D, Caliebe A, Del Greco M F, König IR (2022)
Journal article
Medizinische Genetik

More information: https://doi.org/10.1515/medgen-2022-2139

https://doi.org/10.1515/medgen-2022-2139

Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease
Trinh J, Hicks AA, König IR, Delcambre S, Lüth T, Schaake S, Wasner K, Ghelfi J, Borsche M, Vilariño-Güell C, Hentati F, Germer EL, Bauer P, Takanashi M, Kostić V, Lang AE, Brüggemann N, Pramstaller PP, Pichler I, Rajput A, Hattori N, Farrer MJ, Lohmann K, Weissensteiner H, May P, Klein C, Grünewald A
(2022)
Journal article
Brain

https://doi.org/10.1093/brain/awac464

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers
Castelo-Rueda MP, Zanon A, Gilmozzi V, Lavdas AA, Raftopoulou A, Delcambre S, Del Greco M F, Klein C, Grünewald A, Pramstaller PP, Hicks AA, Pichler I (2022)
Presentation/Speech

Conference: Cell Symposia| Multifaceted Mitochondria | Seville : 6.11.2022 - 8.11.2022

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

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 impact of instruments selection on Mendelian Randomization results: a case study
Bottigliengo D, Caliebe A, König IR, Del Greco M F (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

https://hdl.handle.net/10863/23764

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

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

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

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  • University of Lübeck, Institute of Neurogenetics

  • University of Luxembourg, Luxembourg Centre for Systems Biomedicine

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Maria Paulina Castelo Rueda

Maria Paulina Castelo Rueda

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SENECA

Epigenetics of cellular senescence in aging

Funding: Italy-Austria 2021-2027 (EUTC / EU ...

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