1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Parkinson’s Disease: Linking mitochondria to the immune response

  1. Rebecca L Wallings
  2. Mary K Herrick
  3. Malú Gámez Tansey  Is a corresponding author
  1. Department for Neuroscience, University of Florida College of Medicine, United States
  2. Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, United States
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Cite this article as: eLife 2020;9:e56214 doi: 10.7554/eLife.56214
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Interactions between mitochondrial homeostasis and immune response in a Lrrk2 knockout macrophage.

(Top) Loss of Lrrk2 in mouse macrophages increases DRP1 phosphorylation. This leads to an increase in the level of mitochondrial DNA (mtDNA; red bean-shaped structures) in the cytosol, which activates the cGAS/STING pathway. This, in turn, triggers the phosphorylation of transcription factors that activate the expression of interferon (IFN) response genes in the nucleus, which leads to a lowered response to interferon from these cells. In this situation, antioxidant levels in the cell are low and mitochondrial stress increases. (Bottom) Three different treatments can partially or totally rescue inflammatory deficits in Lrrk2 knockout macrophages. First, treating these macrophages with antioxidants alleviates mitochondrial stress and rescues the normal response to interferon. Second, inhibiting DRP1 phosphorylation decreases fission, lowering the level of mitochondrial DNA (green bean-shaped structures) in the cytosol. This prevents the activation of the cGAS/STING pathway, and consequently, the abnormal activation of interferon response genes. Third (and confirming this finding), removing the cGas gene also mitigates increased interferon stimulated gene expression.

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