Axon Degeneration Mechanisms in Human Disease

Research in our laboratory showed that a preventable mechanism of axon degeneration, known as programmed axon death or Wallerian degeneration, is shared by injury and disease, and is regulated by NAD and related metabolites. Programmed axon death is executed by the NAD-degrading enzyme SARM1, whose activity in axons is kept at a low, safe level by the NAD-synthesising enzyme NMNAT2. When NMNAT2 activity is impaired, or its delivery into axons by axonal transport is blocked, SARM1 becomes activated and axons die. The human consequences include paralysis, gain- or loss of pain (sometimes leading to limb amputation), blindness, movement disorders and dysregulation of vital organs.

 Recent studies show this pathway can be activated by loss- and gain-of-function (LoF, GoF) mutations in NMNAT2 and SARM1 respectively. These gene variants have already been associated with polyneuropathies and ALS, disorders of long human axons but animal data suggest much wider disease relevance, including in Parkinson’s disease, glaucoma, multiple sclerosis, and peripheral neuropathies due to diabetes, cancer chemotherapy, viruses and mutation of other genes. The pathway can also be activated by environmental risk factors, including certain toxins and viruses.

 The Coleman Lab has several PhD and MPhil projects available to enhance understanding of how this pathway contributes to specific human neurological disorders. These studies will help indicate in which diseases, and in which specific patients, SARM1-blocking drugs currently under development can be most effectively targeted to prevent and treat human disease. They will also enhance our understanding of the function and regulation of NMNAT2 and SARM1.