Reference : Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 park...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/44651
Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism
English
Borsche, Max[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany > > > ; Department of Neurology, University of Lübeck , Lübeck, Germany]
Koenig, Inke[Institute of Medical Biometry and Statistics, University of Lübeck , Lübeck, Germany]
Delcambre, Sylvie[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Petrucci, Simona[Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome, Italy > > > ; Division of Medical Genetics, IRCCS-Casa Sollievo della Sofferenza , San Giovanni Rotondo, Italy]
Balck, Alexander[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany > > > ; Department of Neurology, University of Lübeck , Lübeck, Germany]
Brueggemann, Norbert[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany > > > ; Department of Neurology, University of Lübeck , Lübeck, Germany]
Zimprich, Alexander[Department of Neurology, Medical University of Vienna , Vienna, Austria]
Wasner, Kobi[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Deuschle, Christian[Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen , Tübingen, Germany > > > ; German Center for Neurodegenerative Diseases (DZNE), University of Tübingen , Tübingen, Germany]
Badanjak, Katja[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Ghelfi, Jenny[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Gasser, Thomas[Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen , Tübingen, Germany > > > ; German Center for Neurodegenerative Diseases (DZNE), University of Tübingen , Tübingen, Germany]
Kasten, Meike[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany > > > ; Department of Psychiatry, University of Lübeck , Lübeck, Germany]
Rosenstiel, Philip[Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel , Kiel, Germany]
Lohmann, Katja[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany]
Brockmann, Kathrin[Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen , Tübingen, Germany > > > ; German Center for Neurodegenerative Diseases (DZNE), University of Tübingen , Tübingen, Germany]
Valente, Enza Maria[IRCCS Mondino Foundation , Pavia, Italy > > > ; Department of Molecular Medicine, University of Pavia , Pavia, Italy]
Youle, Richard J[Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland, USA]
Grünewald, Anne[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Klein, Christine[Institute of Neurogenetics, University of Lübeck , Lübeck, Germany > > > ; Correspondence to: Christine Klein, MD Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany]
[en] There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.
[University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
