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.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that limits many effective anticancer chemotherapies [1]
These results indicate that our paclitaxel feeding regimen is feasible to develop a peripheral neuropathy phenotype in Drosophila larvae
To understand how PINK1 mitigates paclitaxel-induced thermal hypersensitivity, we examined whether paclitaxel induces mitochondrial dysfunction in our paclitaxelinduced peripheral neuropathy model
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that limits many effective anticancer chemotherapies [1]. Various symptoms arise depending on the type, amount, and duration of the anticancer drug, typical clinical features of CIPN include sensory nerve abnormalities such as paresthesia, allodynia and hyperalgesia [2]. These symptoms may persist for several months to several years after the completion of chemotherapy in up to 30% of patients, and in severe cases, CIPN adversely affects the quality of life of cancer survivors for the lifetime [2]. The major dose-limiting side effect of paclitaxel treatment is painful peripheral neuropathy, which is predominantly sensory [4, 5]
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