Programmed axon degeneration gene variants in human disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Programmed axon degeneration (PAD), or Wallerian degeneration, is a critical pathway for axon breakdown after injury or stress.
• PAD involves nicotinamide adenine dinucleotide (NAD) depletion, influenced by the enzyme NMNAT2 and the NADase SARM1.
• Genetic variations in PAD pathway enzymes are linked to severe neurodegenerative conditions.

Purpose of the Study:

• To review pathogenic variants in key enzymes of the programmed axon degeneration (PAD) pathway.
• To elucidate the specific neurodegenerative phenotypes associated with variants in NAMPT, NMNAT1, NMNAT2, and SARM1.
• To highlight the role of NAD homeostasis in axon survival and neuroprotection.

Main Methods:

• Review of identified pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1.
• Analysis of associated clinical phenotypes, including neuropathies and neurodevelopmental symptoms.
• Examination of SARM1 gain-of-function variants in amyotrophic lateral sclerosis (ALS).

Main Results:

• NAMPT variants are associated with sensory/motor neuropathy and neurodevelopmental issues.
• NMNAT1 variants cause Leber Congenital Amaurosis type 9.
• NMNAT2 variants lead to childhood-onset peripheral neuropathies, and SARM1 variants are linked to ALS.

Conclusions:

• Disruptions in NAD homeostasis due to genetic variants result in distinct neurodegenerative outcomes.
• Studying these rare variants offers insights into PAD mechanisms and neuroprotection.
• Therapeutic strategies targeting the PAD pathway, including SARM1 inhibitors and NAD precursors, show promise for neurodegenerative diseases.