Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration
TL;DR: Analysis of subcellular localization of the overexpressed proteins revealed that the axonal protection phenotype was correlated with localization of NMNAT enzymatic activity to mitochondrial matrix, and isolated mitochondria from mice showing axonalprotection expressed unchanged levels of respiratory chain components, but were capable of increased ATP production.
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Abstract: Studies of naturally occurring mutant mice, wld s , showing delayed Wallerian degeneration phenotype, suggest that axonal degeneration is an active process. We previously showed that increased nicotinamide adenine dinucleotide (NAD)-synthesizing activity by overexpression of nicotinamide mononucleotide adenylyltransferase (NMNAT) is the essential component of the Wld s protein, the expression of which is responsible for the delayed Wallerian degeneration phenotype in wld s mice. Indeed, NMNAT overexpression in cultured neurons provides robust protection to neurites, as well. To examine the effect of NMNAT overexpression in vivo and to analyze the mechanism that causes axonal protection, we generated transgenic mice (Tg) overexpressing NMNAT1 (nuclear isoform), NMNAT3 (mitochondrial isoform), or the Wld s protein bearing a W258A mutation, which disrupts NAD-synthesizing activity of the Wld s protein. Wallerian degeneration delay in NMNAT3-Tg was similar to that in wld s mice, whereas axonal protection in NMNAT1-Tg or Wld s (W258A)-Tg was not detectable. Detailed analysis of subcellular localization of the overexpressed proteins revealed that the axonal protection phenotype was correlated with localization of NMNAT enzymatic activity to mitochondrial matrix. Furthermore, we found that isolated mitochondria from mice showing axonal protection expressed unchanged levels of respiratory chain components, but were capable of increased ATP production. These results suggest that axonal protection by NMNAT expression in neurons is provided by modifying mitochondrial function. Alteration of mitochondrial function may constitute a novel tool for axonal protection, as well as a possible treatment of diseases involving axonopathy.
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Citations
Autophagy in axonal degeneration in glaucomatous optic neuropathy.
TL;DR: The relationship between autophagy and recently reported noteworthy factors including Nmnat, ROCK, and SIRT1 in the degeneration of RGCs and their axons are described and possible mechanisms of axonal protection via modulation of autophagic machinery are proposed.
79
Wallerian-Like Degeneration of Central Neurons After Synchronized and Geometrically Registered Mass Axotomy in a Three-Compartmental Microfluidic Chip
Devrim Kilinc,Jean-Michel Peyrin,Vanessa Soubeyre,Sebastien Magnifico,Laure Saias,Jean-Louis Viovy,Bernard Brugg +6 more
TL;DR: A novel experimental model system, based on microfluidic isolation, which consists of three distinct compartments, interconnected by parallel microchannels allowing axon outgrowth, that reports that mouse embryonic cortical neurons exhibit rapid Wallerian-like distal degeneration but no somatic death following central axotomy.
79
Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma
TL;DR: The role of energy availability and utilization in axon degeneration in glaucoma, a chronic axonopathy of the retinal projection is reviewed.
Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLDS-mediated axon protection independent of axonal mitochondria
Brandon M. Kitay,Ryan McCormack,Yunfang Wang,Pantelis Tsoulfas,Pantelis Tsoulfas,R. Grace Zhai +5 more
TL;DR: An axon self-destruction cascade governing WD is unveiled that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLD(S) (Wallerian degeneration slow)-mediated axon protection.
76
A Model of Toxic Neuropathy in Drosophila Reveals a Role for MORN4 in Promoting Axonal Degeneration
Martha R.C. Bhattacharya,Josiah Gerdts,Sarah A. Naylor,Emily X. Royse,Sarah Y. Ebstein,Yo Sasaki,Jeffrey Milbrandt,Aaron DiAntonio +7 more
TL;DR: A screening platform based on intoxication of Drosophila larvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients, can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies.
74
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