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Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.

ABSTRACT: Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission. We also identified caspases as negative regulators of axon injury-mediated NP, so mitochondrial fission could control NP through caspase activation. In addition to negative regulators of NP, we found that nicotinamide mononucleotide adenylyltransferase (Nmnat) is absolutely required for this type of NP. Increased microtubule dynamics, which has previously been associated with NP, required Nmnat. Indeed Nmnat overexpression was sufficient to induce NP and increase microtubule dynamics in the absence of axon injury. DLK, JNK and fos were also required for NP. Because NP occurs before axon regeneration, and NP seems to be actively downregulated, we tested whether excessive NP might inhibit regeneration. Indeed both Nmnat overexpression and caspase reduction reduced regeneration. In addition, overexpression of fos or JNK extended the timecourse of NP and dampened regeneration in a Nmnat-dependent manner. These data suggest that NP and regeneration are conflicting responses to axon injury, and that therapeutic strategies that boost NP may reduce regeneration.

SUBMITTER: Chen L

PROVIDER: S-EPMC5173288 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.

Chen Li L Nye Derek M DM Stone Michelle C MC Weiner Alexis T AT Gheres Kyle W KW Xiong Xin X Collins Catherine A CA Rolls Melissa M MM

PLoS genetics 20161206 12

Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn ...[more]

PMID: 27923046

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Project description:Houshiheisan, a classic prescription in traditional Chinese medicine, contains Flos Chrysanthemi, Radix Saposhnikoviae, Ramulus Cinnamomi, Rhizoma Chuanxiong, Radix et Rhizoma Asari, Radix Platycodonis, Rhizoma Atractylodis macrocephalae, Poria, Rhizoma Zingiberis, Radix Angelicae sinensis, Radix et Rhizoma Ginseng, Radix Scutellariae and Concha Ostreae. According to traditional Chinese medicine theory, Flos Chrysanthemi, Radix Saposhnikoviae, Ramulus Cinnamomi, Rhizoma Chuanxiong, Radix et Rhizoma Asari and Radix Platycodonis are wind-dispelling drugs; Rhizoma Atractylodis macrocephalae, Poria, Rhizoma Zingiberis, Radix Angelicae sinensis and Radix et Rhizoma Ginseng are deficiency-nourishing drugs. A large number of randomized controlled trials have shown that Houshiheisan is effective in treating stroke, but its mechanism of action is unknown. Axonal remodeling is an important mechanism in neural protection and regeneration. Therefore, this study explored the effect and mechanism of action of Houshiheisan on the repair of axons after cerebral ischemia. Rat models of focal cerebral ischemia were established by ligating the right middle cerebral artery. At 6 hours after model establishment, rats were intragastrically administered 10.5 g/kg Houshiheisan or 7.7 g/kg wind-dispelling drug or 2.59 g/kg deficiency-nourishing drug. These medicines were intragastrically administered as above every 24 hours for 7 consecutive days. Houshiheisan, and its wind-dispelling and deficiency-nourishing components reduced the neurological deficit score and ameliorated axon and neuron lesions after cerebral ischemia. Furthermore, Houshiheisan, and its wind-dispelling and deficiency-nourishing components decreased the expression of proteins that inhibit axonal remodeling: amyloid precursor protein, neurite outgrowth inhibitor protein A (Nogo-A), Rho family small GTPase A (RhoA) and Rho-associated kinase 2 (Rock2), and increased the expression of growth associated protein-43, microtubule-associated protein-2, netrin-1, Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42). The effect of Houshiheisan was stronger than wind-dispelling drugs or deficiency-nourishing drugs alone. In conclusion, Houshiheisan, and wind-dispelling and deficiency-nourishing drugs promote the repair of axons and nerve regeneration after cerebral ischemia through Nogo-A/RhoA/Rock2 and Netrin-1/Rac1/Cdc42 signaling pathways. These effects are strongest with Houshiheisan.

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Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.

Publications

Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.

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