Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT.
Deficits in axonal transport are thought to contribute to the pathology of many neurodegenerative diseases. Expressing the slow Wallerian degeneration protein (Wld(S)) or related nicotinamide mononucleotide adenyltransferases (NmNATs) protects axons against damage from a broad range of insults, but the ability of these proteins to protect against inhibition of axonal transport has received little attention. We set out to determine whether these proteins can protect the axons of cultured hippocampal neurons from damage due to hydrogen peroxide or oxygen-glucose deprivation (OGD) and, in particular, whether they can reduce the damage that these agents cause to the axonal transport machinery. Exposure to these insults inhibited the axonal transport of both mitochondria and of the vesicles that carry axonal membrane proteins; this inhibition occurred hours before the first signs of axonal degeneration. Expressing a cytoplasmically targeted version of NmNAT1 (cytNmNAT1) protected the axons against both insults. It also reduced the inhibition of transport when cells were exposed to hydrogen peroxide and enhanced the recovery of transport following both insults. The protective effects of cytNmNAT1 depend on mitochondrial transport. When mitochondrial transport was inhibited, cytNmNAT1 was unable to protect axons against either insult. The protective effects of mitochondrially targeted NmNAT also were blocked by inhibiting mitochondrial transport. These results establish that NmNAT robustly protects the axonal transport system following exposure to OGD and reactive oxygen species and may offer similar protection in other disease models. Understanding how NmNAT protects the axonal transport system may lead to new strategies for neuroprotection in neurodegenerative diseases.
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239 USA.
Cheng
C
Fang
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239 USA.
Helena
H
Decker
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239 USA. Electronic address: bankerg@ohsu.edu.
Gary
G
Banker
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D051381:Rats; D014855:Wallerian Degeneration / Q000517:prevention & control
D018696:Neuroprotective Agents; D016877:Oxidants; D006861:Hydrogen Peroxide; C529444:NMNAT1 protein, rat; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D005947:Glucose
Axonal transport; Miro; NmNAT1, mitochondria; Oxidative stress; Oxygen-glucose deprivation