[en] Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.
Centre de recherche :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB)
Disciplines :
Génétique & processus génétiques Neurologie
Auteur, co-auteur :
Trinh, Joanne
Hicks, Andrew A.
König, Inke R.
DELCAMBRE, Sylvie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Lüth, Theresa
Schaake, Susen
Wasner, Kobi
GHELFI, Jenny ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Borsche, Max
Vilariño-Güell, Carles
Hentati, Faycel
Germer, Elisabeth L.
Bauer, Peter
Takanashi, Masashi
Kostić, Vladimir
Lang, Anthony E.
Brüggemann, Norbert
Pramstaller, Peter P.
Pichler, Irene
Rajput, Alex
Hattori, Nobutaka
Farrer, Matthew J.
Lohmann, Katja
Weissensteiner, Hansi
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Klein, Christine
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
FNR11250962 - Reduced Penetrance In Hereditary Movement Disorders: Elucidating Mechanisms Of Endogenous Disease Protection P1: Markers And Mechanisms Of Reduced Penetrance In Lrrk2 Mutation Carriers, 2016 (01/01/2017-30/06/2020) - Anne Grünewald
Intitulé du projet de recherche :
ProtectMove
Organisme subsidiant :
Fonds National de la Recherche - FnR (ProtectMove, MiRisk) DFG (ProtectMove) BMBF (MitoPD)
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