PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

Abstract

Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN.

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

“…Older, but not young (6-month vs 2-month) Pink1 knockout mice exhibit increased excitatory neurotransmission, accompanied by increased neurotransmitter release on KCl stimulation without changes in protein expression of synaptic vesicle proteins syntaxin1a, Munc-18 or SNAP25 [ 107 ]. Moreover, Pink1 is able to modulate sensory dendrite pathology in a Drosophila model of chemotherapy-induced neuropathy [ 108 ]. Neurochemical analysis in Pink1 knockout rats showed higher glutamine levels as an indirect measure of glutamate neurotransmission [ 109 ].…”

The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy

“…The w 1118 , ppk-GAL4, ppk 1a -GAL4, UAS-CD4-tdTomato (CD4-tdTom), UAS-mt-Keima, PINK1 RNAi, UAS-GFP dsRNA (BL9331), and UAS-mito-roGFP2-Orp1 lines were described previously [16].…”

“…Paclitaxel (Cayman Chemical Co., Ann Arbor, MI, USA) was administered following a feeding regimen described previously [16]. Briefly, twenty virgin female flies were mated with fifty male flies for 48-72 h, and the embryos were collected for 2-4 h on grape juice agar plates.…”

“…Interestingly, PINK1 expression did not suppress paclitaxelinduced alterations to the sensory dendrite structure of class IV dendritic arborization (C4da) neurons which are responsible for behavioral responses to various noxious stimuli, including high temperatures [17,18]. However, paclitaxel-induced increases in both mitochondrial ROS and mitophagy were significantly suppressed by PINK1 expression [16], suggesting that PINK1 can reduce the mitochondrial dysfunction induced by paclitaxel. Although we observed that PINK1 expression ameliorated paclitaxel-induced mitochondrial dysfunction and attenuated the thermal hyperalgesia phenotype, our previous results also indicated that constitutive PINK1 overexpression led to several side effects.…”

“…We had previously shown that sensory neuron-specific expression of PINK1 significantly ameliorated the thermal hyperalgesia phenotype in a paclitaxel-induced Drosophila larvae CIPN model [16]. Interestingly, PINK1 expression did not suppress paclitaxelinduced alterations to the sensory dendrite structure of class IV dendritic arborization (C4da) neurons which are responsible for behavioral responses to various noxious stimuli, including high temperatures [17,18].…”