Mitochondrial DNA heteroplasmy distinguishes disease manifestation in <i>PINK1</i> / <i>PRKN-</i> 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, F. Hentati, Elisabeth Luisa Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostić, Anthony E. Lang, Norbert Brüggemann, Peter P. Pramstaller, Irene Pichler, Alex Rajput, Nobutaka Hattori, Matthew J. Farrer, Katja Lohmann, Hansi Weißensteiner, Patrick May, Christine Klein, Anne Grünewald
Abstract
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.