NAD⁺, Axonal Maintenance, and Neurological Disease.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Axonal degeneration is implicated in various neurological disorders, including neuropathies and neurodegenerative diseases.
• Wallerian degeneration (WD) is a programmed axonal self-destruction pathway involving nicotinamide adenine dinucleotide (NAD+) metabolism.
• The sterile alpha and TIR motif containing 1 (SARM1) protein acts as a key signal for WD.

Purpose of the Study:

• To explore the complex roles of NAD+ in axonal viability and disease pathogenesis.
• To investigate the regulatory mechanisms of NAD+ metabolism in axonal degeneration.
• To identify potential therapeutic strategies targeting NAD+ metabolism and SARM1 for neurological diseases.

Main Methods:

• Review of existing literature on axonal degeneration, WD, and NAD+ metabolism.
• Analysis of the function of SARM1 as a NAD+ hydrolase and sensor.
• Examination of the regulation of NMNAT2 proteostasis and SARM1 allosteric regulation by NAD+ and NMN.

Main Results:

• SARM1 activation is a central event in WD, regulated by NAD+ metabolism.
• Discoveries highlight the protective roles of WldS and the instructive role of SARM1 in WD.
• Modulators of NAD+ metabolism and SARM1 inhibitors show therapeutic potential.

Conclusions:

• Clarifying the distinct roles of NAD+ metabolism in axonal maintenance versus WD is essential.
• Further research is needed to understand NAD+ metabolism's role in axonal endangerment in various neurological conditions.
• Targeting NAD+ metabolism and SARM1 pathways offers promising avenues for treating neurological diseases involving axonal degeneration.