Dysregulation of the Mitochondrial Unfolded Protein Response Induces Non-Apoptotic Dopaminergic Neurodegeneration inC. elegansModels of Parkinson's Disease

Abstract

Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR). In , mitochondrial damage leads to nuclear translocation of the ATFS-1 transcription factor to activate the UPR After short-term acute stress has been mitigated, the UPR is eventually suppressed to restore homeostasis to hermaphrodites. In contrast, and reflective of the more chronic nature of progressive neurodegenerative disorders such as Parkinson's disease (PD), here, we report the consequences of prolonged, cell-autonomous activation of the UPR in dopaminergic neurons. We reveal that neuronal function and integrity decline rapidly with age, culminating in activity-dependent, non-apoptotic cell death. In a PD-like context wherein transgenic nematodes express the Lewy body constituent protein α-synuclein (αS), we not only find that this protein and its PD-associated disease variants have the capacity to induce the UPR, but also that coexpression of αS and ATFS-1-associated dysregulation of the UPR synergistically potentiate dopaminergic neurotoxicity. This genetic interaction is in parallel to mitophagic pathways dependent on the homolog, which is necessary for cellular resistance to chronic malfunction of the UPR Given the increasingly recognized role of mitochondrial quality control in neurodegenerative diseases, these studies illustrate, for the first time, an insidious aspect of mitochondrial signaling in which the UPR pathway, under disease-associated, context-specific dysregulation, exacerbates disruption of dopaminergic neurons , resulting in the neurodegeneration characteristic of PD. Disruptions or alterations in the activation of pathways that regulate mitochondrial quality control have been linked to neurodegenerative diseases due in part to the central role of mitochondria in metabolism, ROS regulation, and proteostasis. The extent to which these pathways, including the mitochondrial unfolded protein response (UPR) and mitophagy, are active may predict severity and progression of these disorders, as well as sensitivity to compounding stressors. Furthermore, therapeutic strategies that aim to induce these pathways may benefit from increased study into cellular responses that arise from long-term or ectopic stimulation, especially in neuronal compartments. By demonstrating the detrimental consequences of prolonged cellular activation of the UPR, we provide evidence that this pathway is not a universally beneficial mechanism because dysregulation has neurotoxic consequences.

IMPACT OF PHENOLIC ACIDS ON THE ENERGY METABOLISM AND LONGEVITY INC. ELEGANS

“…This appears feasible since a dose-depended effect of PCA to ameliorate rotenone induced toxicity has been shown in PC12 cells [61]. Interestingly, VA significantly upregulated the expression of atfs-1, indicating an increased mitochondrial unfolded protein response, generally associated with increased longevity and age [62,63], as can be further evidenced by our life-and health-span assessment.…”

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

“…Alternatively, other retrograde signaling pathways such as that mediated by ATFS-1 and the mitochondrial unfolded protein response (mtUPR) can also mediate adaptation to mitochondrial stress (85), including stress due to defects in mitophagy machinery (86). However, prolonged cellular activation of the mtUPR has been shown to be maladaptive in a C. elegans model of dopaminergic neurodegeneration (87), suggesting that ultimate role of stress response pathways is context dependent. It is also possible that the single-copy tau mutants do not elicit stress-responses in-and-of themselves, but instead sensitize neurons to additional stressors, consistent with our mitophagy results.…”

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

“…Knockdown of this gene in DNs produced a paradoxical increase in protection against synuclein-dependent neurodegeneration, suggesting that the ATFS-1 signaling pathway may have deleterious effects when chronically activated (Martinez et al, 2017). Similarly, atfs-1 knockdown in animals not treated with nicotine protected DNs from 6-OHDA toxicity ( Figure 6D).…”

“…This relationship, however, has not been previously linked to nicotine-induced neuroprotection. To investigate whether pathways known to mediate responses to mitochondrial stress also modulate the neuroprotective effects of nicotine, we examined four genes shown to influence the mitochondrial stress response and to function in C. elegans DNs, as demonstrated by their effects on -synuclein-dependent neurodegeneration (mcu-1, micu-1, atfs-1, and pink-1) (Martinez, Kim, Ray, Caldwell, & Caldwell, 2015;Martinez et al, 2017).…”

“…For DN-specific RNAi knockdown of genes, we used a sid-1 mutant strain expressing sid-1 only in DNs; this strain is UA202 [sid-1(pk3321); P dat-1 ::GFP::sid-1, P myo-2 ::mCherry #15.1[baIn36]; P dat-1 ::GFP::GFP(vtIs7) (Harrington et al, 2012). RNAi clones were obtained from the Ahringer library (Kamath et al, 2003) except for atfs-1, which was described previously (Kamath et al, 2003;Martinez et al, 2017).…”