Axonal degeneration is an early and likely initiating event in some of the most prevalent neurological diseases, including peripheral neuropathies, traumatic brain injury, Parkinson's disease and glaucoma. Although axon loss is central to many neurological disorders, no treatments currently exist that effectively target axonal breakdown. Axon degeneration is a subcellular self-destructive process that is activated by traumatic, metabolic, and neurodegenerative insults. Conceptually this degeneration program is akin to the apoptotic pathway?it is a biochemical pathway that dismantles injured axons in much the same way that the apoptotic pathway orchestrates the programmed death of dysfunctional cells, although the molecular mechanisms are primarily distinct. Others and we discovered that SARM1 is an essential component of the injury-activated axonal degeneration program. Importantly, SARM1 is also required for axon loss in models of neurological disease, including peripheral neuropathies and traumatic brain injury. Hence, agents that block SARM1 activity are exciting therapeutic candidates for axonal preservation in diseases of axon loss. In the prior funding period we made a major conceptual breakthrough, discovering that SARM1 is a NAD+ cleaving enzyme and, hence, a druggable target in the axon degeneration pathway. However, to exploit the full promise of targeting SARM1 we must understand the molecular mechanisms upstream and downstream of SARM1 enzyme activity. Here we will explore the role of SARM1-derived NAD+ metabolites as biomarkers and mediators of axon degeneration. We will also identify the mechanisms that keep SARM1 `off' in a healthy axon and turn SARM1 `on' in a diseased axon. If successful, these studies will define the molecular mechanisms upstream and downstream of SARM1 enzyme activity and identify novel therapeutic targets for the preservation of axons in neurological diseases.
Axons connect neurons to their targets and enable information transfer. In many neurodegenerative diseases, axon loss is an early event contributing to dysfunction of the nervous system. We have identified SARM1 as a protein that triggers axon loss in injury and disease. Here we will define how SARM1 is activated in unhealthy axons, and discover how activated SARM1 induces axon loss. These new insights could lead to methods to maintain axons and treat a wide variety of neurodegenerative diseases.
|McGill, Bryan E; Barve, Ruteja A; Maloney, Susan E et al. (2018) Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of Ctcf in Camk2a-Cre-Expressing Neurons. J Neurosci 38:200-219|
|Sasaki, Yo; Hackett, Amber R; Kim, Sungsu et al. (2018) Dysregulation of NAD+ Metabolism Induces a Schwann Cell Dedifferentiation Program. J Neurosci 38:6546-6562|
|Essuman, Kow; Summers, Daniel W; Sasaki, Yo et al. (2018) TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes. Curr Biol 28:421-430.e4|
|Summers, Daniel W; Milbrandt, Jeffrey; DiAntonio, Aaron (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. Proc Natl Acad Sci U S A 115:E8746-E8754|
|Essuman, Kow; Summers, Daniel W; Sasaki, Yo et al. (2017) The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron 93:1334-1343.e5|
|Walker, Lauren J; Summers, Daniel W; Sasaki, Yo et al. (2017) MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. Elife 6:|
|Summers, Daniel W; Gibson, Daniel A; DiAntonio, Aaron et al. (2016) SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A 113:E6271-E6280|
|Gerdts, Josiah; Summers, Daniel W; Milbrandt, Jeffrey et al. (2016) Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 89:449-60|
|Geisler, Stefanie; Doan, Ryan A; Strickland, Amy et al. (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139:3092-3108|
|Bhattacharya, Martha R C; Geisler, Stefanie; Pittman, Sara K et al. (2016) TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. J Neurosci 36:4681-9|
Showing the most recent 10 out of 14 publications