Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective

The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson's disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut-brain communication modulates neurotoxicity in a fly model of Parkinson's disease through a mechanism involving mitochondrial dysfunction.

Automated summary

This study reveals that damaged and defective mitochondria can trigger inflammation and lead to intestinal dysfunction, cell death, metabolic reprogramming, and neurotoxicity in a fly model of Parkinson's disease. By suppressing the inflammatory signaling, mitochondrial function can be restored and neuroprotection can be achieved, highlighting the role of gut-brain communication in modulating neurotoxicity in Parkinson's disease.