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Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases
Heather S Loring1, Paul R Thompson1
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA 01605, USA; Program in Chemical Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Abstract:
Wallerian degeneration is a neuronal death pathway that is triggered in response to injury or disease. Death was thought to occur passively until the discovery of a mouse strain, i.e., Wallerian degeneration slow (WLDS), which was resistant to degeneration. Given that the WLDS mouse encodes a gain-of-function fusion protein, its relevance to human disease was limited. The later discovery that SARM1 (sterile alpha and toll/interleukin receptor [TIR] motif-containing protein 1) promotes Wallerian degeneration suggested the existence of a pathway that might be targeted therapeutically. More recently, SARM1 was found to execute degeneration by hydrolyzing NAD+. Notably, SARM1 knockdown or knockout prevents neuron degeneration in response to a range of insults that lead to peripheral neuropathy, traumatic brain injury, and neurodegenerative disease. Here, we discuss the role of SARM1 in Wallerian degeneration and the opportunities to target this enzyme therapeutically.
Insights
Wallerian degeneration, a neuronal death process, is actively promoted by SARM1, an enzyme that hydrolyzes NAD+. Targeting SARM1 offers therapeutic potential for neurological injuries and diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Wallerian degeneration is a neuronal death pathway following injury or disease.
- The Wallerian degeneration slow (WLD S) mouse revealed degeneration is not passive.
- SARM1 (sterile alpha and toll/interleukin receptor [TIR] motif-containing protein 1) was identified as a key promoter of this process.
Purpose of the Study:
- To discuss the role of SARM1 in Wallerian degeneration.
- To explore therapeutic opportunities targeting SARM1.
Main Methods:
- Review of existing literature on Wallerian degeneration and SARM1.
- Analysis of SARM1's enzymatic activity (NAD+ hydrolysis).
- Examination of SARM1's role in various neurological conditions.
Main Results:
- SARM1 actively drives Wallerian degeneration by hydrolyzing NAD+.
- SARM1 knockdown or knockout protects neurons from degeneration caused by various insults.
- These insults include peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases.
Conclusions:
- SARM1 is a critical executioner of Wallerian degeneration.
- Targeting SARM1 presents a promising therapeutic strategy for a range of neurological disorders.
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