Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models.
Jason F CooperEmily MachielaDylan J DuesKatie K SpielbauerMegan M SenchukJeremy M Van RaamsdonkPublished in: Scientific reports (2017)
While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.
Keyphrases
- wild type
- oxidative stress
- uric acid
- endoplasmic reticulum
- cell death
- prefrontal cortex
- dna damage
- endoplasmic reticulum stress
- metabolic syndrome
- ischemia reperfusion injury
- traumatic brain injury
- induced apoptosis
- cell proliferation
- reactive oxygen species
- spinal cord
- poor prognosis
- free survival
- small molecule
- signaling pathway
- long non coding rna