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. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson's disease. 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. 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. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity, 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). 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. 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.

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A transmembrane aspartyl protease termed ␤-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-␤ precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-␤ (A␤) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to A␤ amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and ␣-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of A␤ in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1⌬E9 mice prevents both A␤ deposition and age-associated cognitive abnormalities that occur in this model of A␤ amyloidosis. Moreover, A␤ deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1 Ϫ/Ϫ mice are prevented by coexpressing APPswe;PS1⌬E9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate A␤ amyloidosis in AD.