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.

Keywords: Sarmoptosis; DLK kinase; PHR1 ligase; NMNAT2; NAD+.

Figure 1. A Unified Model of the Axon Degeneration Pathway and Sites for Therapeutic Intervention

The SARM1 NADase is the central executioner of the axon degeneration pathway. Upon activation, SARM1 triggers NAD⁺ depletion, which elicits a metabolic crisis in the axon and subsequent axon degeneration. SARM1 activation is blocked in the presence of axonal NMNAT2, which is a labile protein that must be constantly delivered via fast axonal transport from the cell body. Neuronal injury and disease can interrupt delivery of NMNAT2 to the axon, allowing for SARM1 activation and induction of axon degeneration. The turnover of axonal NMNAT2 is promoted by the activity of the neuronal stress kinases DLK and LZK as well as the PHR1 ubiquitin ligase complex. There are a number of potential sites of therapeutic intervention in this pathway (red). These include inhibitors of the SARM1 NADase, dominant negative versions of SARM1 that block its activation, kinase inhibitors of DLK/LZK, and NAD⁺ precursors to help maintain NAD⁺ levels.