TY - JOUR T1 - Akt Suppresses Retrograde Degeneration of Dopaminergic Axons by Inhibition of Macroautophagy JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2125 LP - 2135 DO - 10.1523/JNEUROSCI.5519-10.2011 VL - 31 IS - 6 AU - Hsiao-Chun Cheng AU - Sang Ryong Kim AU - Tinmarla F. Oo AU - Tatyana Kareva AU - Olga Yarygina AU - Margarita Rzhetskaya AU - Chuansong Wang AU - Matthew During AU - Zsolt Talloczy AU - Keiji Tanaka AU - Masaaki Komatsu AU - Kazuto Kobayashi AU - Hideyuki Okano AU - Nikolai Kholodilov AU - Robert E. Burke Y1 - 2011/02/09 UR - http://www.jneurosci.org/content/31/6/2125.abstract N2 - 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. ER -