Article (Scientific journals)
Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease
Trinh, Joanne; Hicks, Andrew A.; König, Inke R. et al.
2023In Brain, 146 (7), p. 2753–2765
Peer reviewed
 

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Abstract :
[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.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB)
Disciplines :
Genetics & genetic processes
Neurology
Author, co-author :
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
More authors (17 more) Less
External co-authors :
yes
Language :
English
Title :
Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease
Publication date :
July 2023
Journal title :
Brain
ISSN :
0006-8950
Volume :
146
Issue :
7
Pages :
2753–2765
Peer reviewed :
Peer reviewed
Focus Area :
Systems Biomedicine
FnR Project :
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
Name of the research project :
ProtectMove
Funders :
Fonds National de la Recherche - FnR (ProtectMove, MiRisk)
DFG (ProtectMove)
BMBF (MitoPD)
Commentary :
awac464
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since 19 December 2022

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