microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain

PROJECT SUMMARY Peripheral neuropathy and neuropathy pain can be caused by a myriad of genetic and environment factors as well as therapeutic or recreational drug use. Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting neurotoxic side effect of standard chemotherapy regiments. Over 68% of cancer patients

experience neuropathic symptoms after chemotherapy, and that contributes to a significant percent of the population that suffer from chronic pain and often resort to opioid use. Peripheral neuropathy is closely associated with Alzheimer’s related dementia. Specifically, a negative correlation between the severity of

peripheral neuropathy and cognitive performance has been reported in patients with dementia. The mechanisms of CIPN and Alzheimer’s related neuropathy intersect at the dysregulation of neuronal microtubules. CIPN is caused by microtubule-targeting chemo drugs, while a major pathology in AD is the dysregulation of microtubule

associated protein Tau (tauopathy). There is an urgent need to understand the in vivo mechanisms of CIPN and AD related peripheral neuropathy. Recently, we have optimized a model of peripheral neuropathy using Drosophila larvae that recapitulates salient behavioral, physiological, and cellular aspects of sensory dysfunction.

Our work using this model has uncovered a new mechanism underlying peripheral neuropathy and identified a neuroprotective protein NMNAT with promising potential for mitigating neuropathic pain. Our preliminary studies have identified several natural compounds that potentially upregulate NMNAT transcription and discovered the

exciting role of microRNAs in regulating both the pre-mRNA splicing and mature mRNA stability. The aims of the parent R33 grant include, (1) test the neuroprotective activity of 9 microRNAs that regulate nociceptive hypersensitivity and pain, (2) characterize the molecular pharmacology of 13 natural compounds in regulating

NMNAT expression and enhancing neuroprotection against peripheral neuropathy and chronic pain. The objectives for the supplement application are to expand our testing portfolio to include genetic models of Alzheimer’s disease and identify microRNAs and natural compounds that mitigate peripheral neuropathy in AD.

We have established Tauopathy models that recapitulate cellular pathology of Alzheimer’s including filamentous accumulation of hyperphosphorylated Tau (pTau), neuronal degeneration, impaired nervous system physiology, and shorted survival. Our preliminary pain behavior studies in AD models have observed a hypersensitivity to

pain in mutant hTau (hTauR406W) expressing nociceptors, consistent with clinical presentation of peripheral neuropathy in AD patients. We propose to test our hypothesis that the neuronal microtubule dysregulation in nociceptor neurons is a shared cellular mechanism underlying CIPN and AD induced pain. The proposed

supplement work is within the scope of the parent R33 project but expands the outcome to include I) mechanistic characterization of microRNAs and natural compounds that augment NMNAT-mediate protection against neuropathic pain in AD, and II) identify shared cellular mechanisms between CIPN and AD.