Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy

Hsiao Chun Cheng, Sang Ryong Kim, Tinmarla F. Oo, Tatyana Kareva, Olga Yarygina, Margarita Rzhetskaya, Chuansong Wang, Matthew During, Zsolt Talloczy, Keiji Tanaka, Masaaki Komatsu, Kazuto Kobayashi, Hideyuki Okano, Nikolai Kholodilov, Robert E. Burke

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99 Citations (Scopus)

Abstract

Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.

Original languageEnglish
Pages (from-to)2125-2135
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number6
DOIs
Publication statusPublished - 2011 Feb 9

ASJC Scopus subject areas

  • Neuroscience(all)

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    Cheng, H. C., Kim, S. R., Oo, T. F., Kareva, T., Yarygina, O., Rzhetskaya, M., Wang, C., During, M., Talloczy, Z., Tanaka, K., Komatsu, M., Kobayashi, K., Okano, H., Kholodilov, N., & Burke, R. E. (2011). Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. Journal of Neuroscience, 31(6), 2125-2135. https://doi.org/10.1523/JNEUROSCI.5519-10.2011