Advisor(s)
Dr. Daniela Menichella; Northwestern University, Feinberg Medical School
Dr. Dale George; Northwestern University, Feinberg Medical School
Discipline
Medical and Health Sciences
Start Date
21-4-2021 10:45 AM
End Date
21-4-2021 11:05 AM
Abstract
Painful Diabetic Neuropathy (PDN) affects 25% of diabetic patients and is a chronic disorder with a major effect on quality of life and health care costs. It can be characterized by dorsal root ganglion (DRG) nociceptor hyperexcitability, calcium overload, axonal degeneration, and loss of cutaneous intervention. Currently, the molecular mechanisms contributing to neuropathic pain in PDN are still unclear. We have shown a path forward for improving treatments.
Through quantitative proteomic analyses, we discovered that in mice with PDN induced by a high fat diet (HFD), mitochondria proteins are expressed differentially in DRG nociceptor. Electron microscopy indicated mitochondrial fragmentation and In vivo calcium imaging indicated elevated calcium signaling. Particularly, when the mitochondrial calcium uniporter (MCU) was removed from the neurons, axonal degeneration was reversed, mechanical allodynia was prevented, and normal mitochondrial morphology was restored. These findings point to a molecular pathway that connects neuropathic pain to axonal degeneration in PDN patients. Specifically, increased calcium penetration into mitochondria mediated by the MCU complex, resulting in increased calcium-dependent mitochondrial fission and eventually leading to axonal degeneration and neuropathic pain in PDN, may be a result of nociceptor hyperexcitability and the subsequent increased intracellular calcium concentrations.
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Understanding Molecular Pathways Underlying Axonal Degradation in Painful Diabetic Neuropathy
Painful Diabetic Neuropathy (PDN) affects 25% of diabetic patients and is a chronic disorder with a major effect on quality of life and health care costs. It can be characterized by dorsal root ganglion (DRG) nociceptor hyperexcitability, calcium overload, axonal degeneration, and loss of cutaneous intervention. Currently, the molecular mechanisms contributing to neuropathic pain in PDN are still unclear. We have shown a path forward for improving treatments.
Through quantitative proteomic analyses, we discovered that in mice with PDN induced by a high fat diet (HFD), mitochondria proteins are expressed differentially in DRG nociceptor. Electron microscopy indicated mitochondrial fragmentation and In vivo calcium imaging indicated elevated calcium signaling. Particularly, when the mitochondrial calcium uniporter (MCU) was removed from the neurons, axonal degeneration was reversed, mechanical allodynia was prevented, and normal mitochondrial morphology was restored. These findings point to a molecular pathway that connects neuropathic pain to axonal degeneration in PDN patients. Specifically, increased calcium penetration into mitochondria mediated by the MCU complex, resulting in increased calcium-dependent mitochondrial fission and eventually leading to axonal degeneration and neuropathic pain in PDN, may be a result of nociceptor hyperexcitability and the subsequent increased intracellular calcium concentrations.