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

Joanne Trinh, Andrew A Hicks, Inke R König, Sylvie Delcambre, Theresa Lüth, Susen Schaake, Kobi Wasner, Jenny Ghelfi, Max Borsche, Carles Vilariño-Güell, Faycel Hentati, Elisabeth L Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostić, Anthony E Lang, Norbert Brüggemann, Peter P Pramstaller, Irene Pichler, Alex RajputNobutaka Hattori, Matthew J Farrer, Katja Lohmann, Hansi Weissensteiner, Patrick May, Christine Klein, Anne Grünewald


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 integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA 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 mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner.

Original languageEnglish
JournalBrain : a journal of neurology
Issue number7
Pages (from-to)2753-2765
Number of pages13
Publication statusPublished - 03.07.2023

Research Areas and Centers

  • Research Area: Medical Genetics

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