Axon degeneration: Mechanisms and implications of a distinct program from cell death.
Axon degeneration has been proposed to be a new therapeutic target for neurodegenerative diseases, because it usually occurs earlier than neuronal cell body death with a distinct active program from apoptosis and necrosis. Overexpression of Wld(S) or Nmnats (nicotinamide mononucleotide adenylytransferase, EC2.7.7.1) has been demonstrated to delay axon degeneration initiated by various insults. NAD synthesis activity of Wld(S) and Nmnats was shown to be responsible for their axon-protective function. The mitochondrial Nmnat3 and cytoplasm-localized mutants of Wld(S) and Nmnat1 have similar or even stronger effect than Wld(S) to delay axon degeneration, which suggest that increased mitochondrial or local NAD synthesis might contribute to the protective function of Wld(S) and Nmnats. Further studies show NAD synthesis pathway and ubiquitin proteasome system play important roles in delaying axon degeneration. Wld(S) mice are resistant to a variety of neurodegenerative diseases, but the role of Nmnats in neurodegenerative diseases are largely unknown. NAD plays key roles in energy metabolism, mitochondrial functions and aging, and is suggested to be involved in neuron degenerative diseases. Future studies to identify the upstream factors inducing NAD depletion and the downstream NAD effectors responsible for the axon-protective function will provide more meaningful insights into the molecular mechanisms of axon degeneration in neurodegenerative diseases.
Yan
Tingting
T
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Feng
Yan
Y
Zhai
Qiwei
Q
D000818:Animals; D001369:Axons / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D009410:Nerve Degeneration / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000502:physiology; D014855:Wallerian Degeneration / Q000473:pathology*
D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse; C484009:NMNAT3 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase