Regulation of axonal degeneration by the DLK kinase

Project Summary/Abstract: Axonal degeneration is an early and likely initiating event in many of the most prevalent neurodegenerative diseases. DLK is a major neuronal stress kinase that we identified as the first gene required for pathological axon degeneration. Recently we defined the mechanism: DLK promotes the turnover of the axon maintenance factors NMNAT2 and stathmin2 (STMN2). DLK is activated in animal models of both Alzheimer's Disease and ALS and there are strong data that DLK is also activated in patients with these degenerative disorders. While other labs focus on DLK pro-apoptotic signaling, we demonstrated an independent function for DLK in stimulating SARM1-dependent axon loss. In these studies, we identified STMN2 as an axonal maintenance factor—loss of STMN2 promotes axon degeneration and increased levels of STMN2 inhibits axon degeneration. Recently, two prominent papers identified STMN2 as the major transcript misspliced and downregulated by TDP-43 dysfunction in human iPSCs as well as from spinal cords of ALS patients. TDP-43 dysregulation is an important cause of both frontotemporal dementia and ALS and has recently been implicated in more common dementias. Indeed, STMN2 is one of the most downregulated transcripts in neurons from Alzheimer's patients. The identification of STMN2 as a major target of both TDP-43 dysregulation and DLK activation, two mechanisms implicated in both dementias and ALS, identifies downregulation of STMN2 as a candidate mechanism promoting axon loss in these neurodegenerative diseases. These findings motivate our efforts to define the function of STMN2 for axonal maintenance. While it is known that STMN2 is a stathmin family member that regulates microtubule dynamics, it is not known how STMN2 promotes axon maintenance or the in vivo function of STMN2 for axon survival in health, injury, and disease. Here we will test the hypothesis that STMN2 promotes the activity of the axon maintenance factor NMNAT2 to inhibit the activity of SARM1, the executioner of pathological axon degeneration, and in vivo helps regulate the choice between axon survival and self-destruction in injury and disease. If successful, these studies will define the mechanism by which STMN2 promotes axonal survival and identify STMN2 as a therapeutic target in neurodegenerative disease.