The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

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.

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

“…Release of mtDNA into the cytosol, subsequent interaction of mtDNA with cGAS, and induction of IFNβ expression is also observed in mouse models of macular degeneration [ 199 ] and upon herpes virus infection [ 200 ]. Surprisingly, Whitworth and colleagues showed that knockdown of Sting or its downstream effector Relish using RNAi (in vivo), is insufficient to suppress the locomotor deficits or mitochondrial disruption in Pink1 or Parkin Drosophila mutants [ 201 ]. Furthermore, Sting loss does not affect the behavioural phenotypes associated with a Drosophila mtDNA mutator model, nor the combined effect of mtDNA mutations in a Parkin background, concluding that phenotypes associated with loss of Pink1/Parkin are not universally due to aberrant activation of the Sting pathway [ 201 ].…”

“…Surprisingly, Whitworth and colleagues showed that knockdown of Sting or its downstream effector Relish using RNAi (in vivo), is insufficient to suppress the locomotor deficits or mitochondrial disruption in Pink1 or Parkin Drosophila mutants [ 201 ]. Furthermore, Sting loss does not affect the behavioural phenotypes associated with a Drosophila mtDNA mutator model, nor the combined effect of mtDNA mutations in a Parkin background, concluding that phenotypes associated with loss of Pink1/Parkin are not universally due to aberrant activation of the Sting pathway [ 201 ]. Not only dysregulation of mitochondrial function promotes inflammation, but also inflammation itself leads to mitochondrial dysfunction suggesting the existent of a pro-inflammatory loop with mitochondria playing a central role.…”

The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

“…Consequently, ablation of STING prevented the inflammatory response and the accompanying neurodegenerative phenotypes [ 201 ]. D. melanogaster carries a fly ortholog of STING (Sting) [ 202 ]; however, loss of Drosophila Sting fails to suppress the behavioral and mitochondrial defects in pink1 - and parkin -mutant flies [ 203 ]. Hence, flies can be successfully used for general mechanisms, but studies in mammalian/human systems are necessary to validate the relevance in the disease context and to test specific human functions.…”

The effect of E-liquid exposure on Caenorhabditis elegans

“…Mutations in mitochondrial DNA and in PINK1appear to be more frequent in mice exposed to nicotine containing e-cigarettes [38]. There is recent work connecting PINK1 and mitochondrial stress with the disruption to innate immunity and the STING pathway and this if conserved in C.elegans, may provide some explanation for the effects we see [16] [39].…”