What Is the Role of the Cytosolic DNA Response in Neurodegeneration?

Detection of cytosolic DNA triggers an innate immune response that leads to neuroinflammation. The sources of such DNA include viral or bacterial pathogens as well as nuclear and mitochondrial DNA (mtDNA) released in pathologic conditions.1 Sensing of cytosolic DNA triggers a signal mediated by cyclic GMP-AMP synthase (cGAS) and the stimulator of interferon (IFN) genes (STING) protein, resulting in activation of type I IFNs (IFN-I) and secretion of proinflammatory cytokines.2-5 Whereas the cGAS–STING pathway mediates immunosurveillance that is often neuroprotective, for example against herpes simplex virus type 1 infection, its excessive engagement can be deleterious and promote age-related neuroinflammation and neurodegeneration.1,6 For example, mitochondrial stress due to impaired mitophagy stimulates STING-mediated IFN-I responses.7 Detection of mtDNA released from mitochondria in response to accumulation of transactivation DNA binding protein of 43 kD (TDP-43) activates the STING pathway, leading to neuroinflammation and neurodegeneration in amyotrophic lateral sclerosis (ALS).8 The cGAS-STING pathway is thus a potential target for neuroprotective therapy.1,9