Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

[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

More authors (17 more)

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 :

Pages :

2753–2765

Peer reviewed :

Peer reviewed

Focus Area :

Systems Biomedicine

Additional URL :

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

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

Available on ORBilu :

since 19 December 2022

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