Abstract
Although serum from patients with Parkinson’s disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown 1 . Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease 2,3 . Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy 4 . The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson’s-disease-relevant phenotypes 5–7 . Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity 8–12 , suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn −/− and Pink1 −/− mice following exhaustive exercise and in Prkn −/− ;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA) 13,14 . Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA 15,16 . The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn −/− ;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.
| Original language | English |
|---|---|
| Journal | Nature |
| Volume | 561 |
| Issue number | 7722 |
| Pages (from-to) | 258-262 |
| Number of pages | 5 |
| ISSN | 0028-0836 |
| DOIs | |
| Publication status | Published - 13.09.2018 |
Funding
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 2Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. 3Transgenics Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA. 4Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 5The Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 6Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 7Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. *e-mail: [email protected] Acknowledgements We thank the animal husbandry staff at NINDS and the staff of the Murine Phenotyping Core Facility at NHLBI; the Clinical Pathology Group in the Cellular & Molecular Pathology Branch at NIEHS for serum creatine kinase; K. Gerrish and B. Elgart from the NIEHS Molecular Genomics Core for serum mitochondrial and nuclear DNA isolation and quantification; J. Vargas and S. Humble for experimental assistance and T. Finkel, J. Kowalak, A. Oberst and M. Ward for helpful suggestions. This work was supported by the NINDS Intramural Research Program (R.J.Y.), NIH Intramural Research Program 1ZIAES10328601 (J.M.), the NIA Intramural Research Program (H.C.) the DFG FOR2488; P2 and a Pilot Grant from the Excellence Cluster Inflammation at Interfaces (C.K.), and by a career development award from the Hermann and Lilly Schilling Foundation (C.K.).
Research Areas and Centers
- Research Area: Medical Genetics
