Abstract
Mutations in PINK1 and Parkin/PRKN cause the degeneration of dopaminergic neurons in familial forms of Parkinson’s disease but the precise pathogenic mechanisms are unknown. The PINK1/Parkin pathway has been described to play a central role in mitochondrial homeostasis by signalling the targeted destruction of damaged mitochondria, however, how disrupting this process leads to neuronal death was unclear until recently. An elegant study in mice revealed that the loss of Pink1 or Prkn coupled with an additional mitochondrial stress resulted in the aberrant activation of the innate immune signalling, mediated via the cGAS/STING pathway, causing degeneration of dopaminergic neurons and motor impairment. Genetic knockout of Sting was sufficient to completely prevent neurodegeneration and accompanying motor deficits. To determine whether Sting plays a conserved role in Pink1/parkin related pathology, we tested for genetic interactions between Sting and Pink1/parkin in Drosophila. Surprisingly, we found that loss of Sting, or its downstream effector Relish, was insufficient to suppress the behavioural deficits or mitochondria disruption in the Pink1/parkin mutants. Thus, we conclude that phenotypes associated with loss of Pink1/parkin are not universally due to aberrant activation of the STING pathway.
Highlights
Loss of function mutations in PINK1 and PRKN cause familial parkinsonism, an incurable neurodegenerative disorder predominantly associated with the progressive loss of dopaminergic neurons in substantia nigra leading to loss of motor control
The molecular details of PINK1/Parkin-induced mitophagy are well characterized in cultured cells, relatively little is known about mitophagy under physiological conditions in vivo[3,4,5]
While tremendous advances have been made in uncovering the molecular mechanisms of PINK1/Parkin function in vitro and in cell culture models, understanding the consequences of this dysfunction on neuronal demise must be studied in vivo, in the complex milieu of organismal biology
Summary
Loss of function mutations in PINK1 and PRKN cause familial parkinsonism, an incurable neurodegenerative disorder predominantly associated with the progressive loss of dopaminergic neurons in substantia nigra leading to loss of motor control. One study used a mass spectrometry-based analysis of mitochondrial protein turnover in Drosophila[6], which revealed that fly PINK1 and Parkin selectively affect the degradation of certain mitochondrial proteins under physiological conditions Another found that loss of Prkn in mice, which alone has very little phenotype[7,8], exacerbated the phenotypic effects of a mitochondrial DNA mutator strain, provoking loss of dopaminergic neurons and motor deficits[9]. A subsequent study shed light on the mechanism by which loss of Pink1/Prkn leads to neurodegeneration in the presence of mtDNA mutations, or upon exposure to exhaustive exercise, as chronic or acute www.nature.com/scientificreports mitochondrial stresses, respectively[10] This demonstrated that in the absence of Pink1/Prkn these mitochondrial stresses cause an aberrant inflammatory response mediated by the STING pathway, presumably via the release of mtDNA into the cytosol. While aberrant activation of the IMD-Relish pathway has been shown to cause neurodegeneration and shortened lifespan in Drosophila[15], transcriptional profiling has shown that innate immune signalling pathways are ectopically active in Drosophila parkin and Pink[1] mutants[16,17]
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