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@ARTICLE{Borsche:164313,
      author       = {Borsche, Max and König, Inke R and Delcambre, Sylvie and
                      Petrucci, Simona and Balck, Alexander and Brüggemann,
                      Norbert and Zimprich, Alexander and Wasner, Kobi and
                      Pereira, Sandro L and Avenali, Micol and Deuschle, Christian
                      and Badanjak, Katja and Ghelfi, Jenny and Gasser, Thomas and
                      Kasten, Meike and Rosenstiel, Philip and Lohmann, Katja and
                      Brockmann, Kathrin and Valente, Enza Maria and Youle,
                      Richard J and Grünewald, Anne and Klein, Christine},
      title        = {{M}itochondrial damage-associated inflammation highlights
                      biomarkers in {PRKN}/{PINK}1 parkinsonism},
      journal      = {Brain},
      volume       = {143},
      number       = {10},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2022-00967},
      pages        = {3041 - 3051},
      year         = {2020},
      abstract     = {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.},
      keywords     = {Adult / Aged / Biomarkers: blood / Cross-Sectional Studies
                      / DNA, Mitochondrial: blood / Female / Humans /
                      Inflammation: blood / Inflammation: genetics /
                      Interleukin-6: blood / Male / Middle Aged / Parkinsonian
                      Disorders: blood / Parkinsonian Disorders: genetics /
                      Protein Kinases: genetics / Retrospective Studies /
                      Ubiquitin-Protein Ligases: genetics},
      cin          = {Biobanking Facility Tübingen / AG Gasser},
      ddc          = {610},
      cid          = {I:(DE-2719)1240004 / I:(DE-2719)1210000},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7586086},
      pubmed       = {pmid:33029617},
      doi          = {10.1093/brain/awaa246},
      url          = {https://pub.dzne.de/record/164313},
}