Axon degeneration: mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy

Abstract

Peripheral neuropathy is the most common neurodegenerative disease affecting hundreds of millions of patients worldwide and is an important cause of chronic pain. Typical peripheral neuropathies are characterized by dysesthesias including numbness, crawling skin, a sensation of “pins and needles,” and burning and stabbing pain. In addition, peripheral neuropathy can affect the motor and autonomic systems leading to symptoms such as weakness, constipation, and dysregulation of blood pressure. Peripheral neuropathies can be either hereditary or acquired and are a common consequence of diabetes and treatment with chemotherapy agents. Many neuropathies are due to degeneration of long axons; however, the mechanisms driving axon loss were unknown, and so no therapies are available to preserve vulnerable axons and prevent the development of peripheral neuropathy. With the recent identification of SARM1 as an injury-activated NADase enzyme that triggers axon degeneration, there is now a coherent picture emerging for the mechanism of axonal self-destruction. Here, we will present evidence that inhibiting the SARM1 pathway can prevent the development of peripheral neuropathy, describe the emerging mechanistic understanding of the axon degeneration program, and discuss how these mechanistic insights may be translated to the clinic for the prevention and treatment of peripheral neuropathy and other neurodegenerative disorders.

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

“…It acts by blocking the activation of wild-type SARM-1, and this protects axons from damage. Gene therapy using AAV-mediated delivery of this SARM-1 dominant-negative molecule provided long-lasting axonal protection [114]. In addition, SARM1-mediated NADH dehydrogenase subunit I (NAD1) destruction and loss is compensated by the development of NAD1 precursors, which have the potential ability to protect axons.…”

“…In addition, SARM1-mediated NADH dehydrogenase subunit I (NAD1) destruction and loss is compensated by the development of NAD1 precursors, which have the potential ability to protect axons. These NAD1 precursors are natural products that have potential utility in CIPN prevention [114]. In addition to the direct influence on SARM-1, targeting the upstream pathways regulating SARM-1 to prevent CIPN is of interest.…”

“…Efforts have been made to boost the function and increase the expression of nicotinamide nucleotide adenylyltransferase 2 (NMNAT2). Targeting the degradation of NMNAT2 might also be an alternative for neuropathy [114][115][116].…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…The loss of myelin and changes to the axonal cytoskeleton may alter the structure and impair the function of peripheral nerves, thus leading to the development of sensory and motor peripheral neuropathy and altered pain perception. The molecular mechanisms of these phenomena are not fully established [43,63,67].…”

“…Recent studies have also identified a new molecular mechanism involving sterile alpha and TIR motif-containing protein 1 (SARM1) as an injury-inducible NADase that triggers axonal loss [9,67]. The activation of SARM1 has been shown to contribute to Wallerian degeneration, a phenomenon that occurs during axonal degeneration [72].…”