Maintaining energy homeostasis is an essential component of Wlds-mediated axon protection

NEUROBIOLOGY OF DISEASE

卷:59

Article

Shen, Hua^1,2  Hyrc, Krzysztof L.^1,2,3  Goldberg, Mark P.^1,2 

[1] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Alafi Neuroimaging Lab, St Louis, MO 63110 USA

关键词: Axon injury;    Wld(s);    Energy deprivation;    ATP;    NMNAT;    Calcium;    Bioenergetics;   

DOI  :  10.1016/j.nbd.2013.07.007

来源: Elsevier

【 摘 要 】

Wld(s) mutation protects axons from degeneration in diverse experimental models of neurological disorders, suggesting that the mutation might act on a key step shared by different axon degeneration pathways. Here we test the hypothesis that Wld(s) protects axons by preventing energy deficiency commonly encountered in many diseases. We subjected compartmentally cultured, mouse cortical axons to energy deprivation with 6 mM azide and zero glucose. In wild-type (WO culture, the treatment, which reduced axon ATP level ([ATP](axon)) by 65%, caused immediate axon depolarization followed by gradual free calcium accumulation and subsequent irreversible axon damage. The calcium accumulation resulted from calcium influx partially via L-type voltage-gated calcium channel (L-VGCC). Blocking L-VGCC with nimodipine reduced calcium accumulation and protected axons. Without altering baseline [ATP]axon, the presence of Wld(s) mutation significantly reduced the axon ATP loss and depolarization, restrained the subsequent calcium accumulation, and protected axons against energy deprivation. Wld(s) neurons possessed higher than normal nicotinamide mononudeotide adenylyltransferase (NMNAT) activity. The intrinsic Wld(s) NMNAT activity was required for the Wld(s)-mediated energy preservation and axon protection during but not prior to energy deprivation. NMNAT catalyzes the reversible reaction that produces nicotinamide adenine dinudeotide (NAD) from nicotinamide mononudeotide (NMN). Interestingly, preventing the production of NAD from NMN with FK866 increased [ATP](axon) and protected axons from energy deprivation. These results indicate that the Wld(s) mutation depends on its intrinsic Wld(s) NMNAT activity and the subsequent increase in axon ATP but not NAD to protect axons, implicating a novel role of Wld(s) NMNAT in axon bioenergetics and protection. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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