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Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT.

ABSTRACT: 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.

SUBMITTER: Fang C

PROVIDER: S-EPMC4106704 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT.

Fang Cheng C Decker Helena H Banker Gary G

Neurobiology of disease 20140428

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 hippocam ...[more]

PMID: 24787896

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Project description:Neurodevelopment, plasticity, and cognition are integral with functional directional transport in neuronal axons that occurs along a unique network of discontinuous polar microtubule (MT) bundles. Axonopathies are caused by brain trauma and genetic diseases that perturb or disrupt the axon MT infrastructure and, with it, the dynamic interplay of motor proteins and cargo essential for axonal maintenance and neuronal signaling. The inability to visualize and quantify normal and altered nanoscale spatio-temporal dynamic transport events prevents a full mechanistic understanding of injury, disease progression, and recovery. To address this gap, we generated DyNAMO, a Dynamic Nanoscale Axonal MT Organization model, which is a biologically realistic theoretical axon framework. We use DyNAMO to experimentally simulate multi-kinesin traffic response to focused or distributed tractable injury parameters, which are MT network perturbations affecting MT lengths and multi-MT staggering. We track kinesins with different motility and processivity, as well as their influx rates, in-transit dissociation and reassociation from inter-MT reservoirs, progression, and quantify and spatially represent motor output ratios. DyNAMO demonstrates, in detail, the complex interplay of mixed motor types, crowding, kinesin off/on dissociation and reassociation, and injury consequences of forced intermingling. Stalled forward progression with different injury states is seen as persistent dynamicity of kinesins transiting between MTs and inter-MT reservoirs. DyNAMO analysis provides novel insights and quantification of axonal injury scenarios, including local injury-affected ATP levels, as well as relates these to influences on signaling outputs, including patterns of gating, waves, and pattern switching. The DyNAMO model significantly expands the network of heuristic and mathematical analysis of neuronal functions relevant to axonopathies, diagnostics, and treatment strategies.

Dataset Information

Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT.

Publications

Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT.

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