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

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.