Programmed axon degeneration gene variants in human disease - PubMed
3 hours ago
- #NAD-metabolism
- #neurodegenerative-diseases
- #axon-degeneration
- Programmed axon degeneration (PAD) is a conserved pathway for axon breakdown after injury or metabolic stress.
- PAD involves NAD depletion due to loss of NMNAT2 and activation of SARM1, an NADase.
- Pathogenic variants in PAD genes like NAMPT, NMNAT1, NMNAT2, and SARM1 are linked to neurodegenerative diseases.
- NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms.
- NMNAT1 variants are associated with Leber Congenital Amaurosis type 9.
- NMNAT2 variants lead to peripheral neuropathies starting in childhood.
- SARM1 gain-of-function variants, with active NADase, are enriched in amyotrophic lateral sclerosis patients.
- Maintaining NAD homeostasis is crucial for axon survival; disruption causes neurodegeneration.
- Understanding these variants provides insights into PAD mechanisms and supports neuroprotective therapies.
- Current therapies include SARM1 inhibitors in trials, gene therapy, and NAD precursor supplementation.