Whether activation of the innate immune response is protective or destructive in neurodegenerative diseases remains unclear. Using a C. elegans model of rotenone-induced dopaminergic neurodegeneration, we show that activation of the innate immune response through
p38 MAPK and the CREB/ATF-2 like transcription factor ATF-7 can protect animals from dopaminergic neuron degeneration. Rotenone treatment triggers the phosphorylation of
p38 MAPK and upregulation of ATF-7 target genes. Downregulating
p38 MAPK or ATF-7 exacerbates rotenone-induced neurodegeneration. In contrast, overexpressing active, but not dead
p38 MAPK kinase in peripheral tissue, or ATF-7 in intestinal tissue, protects animals from rotenone-induced neurodegeneration. ATF-7-mediated innate immune response protects against rotenone-induced neurodegeneration by stimulating autophagy and modulating the levels of the ATG8/MAP-LC3 orthologue LGG-1. Preliminary data suggests that knockdown of ATF-7 increases the accumulation of fragmented mitochondria consistent with defective mitophagy. We propose that the activation of the
p38 MAPK dependent innate immune response, that can be initiated by disruption of mitochondrial complex I which accompanies rotenone treatment, is part of a mitochondrial surveillance mechanism, whereby disruption of mitochondrial complex I triggers the clearance of dysfunctional mitochondria by mobilizing autophagy, thereby maintaining homeostasis.