title: Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy.
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.
authors.affiliation: Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Cheng
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Kim
authors.forename: Tinmarla F
authors.initials: TF
authors.lastname: Oo
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kareva
authors.forename: Olga
authors.initials: O
authors.lastname: Yarygina
authors.forename: Margarita
authors.initials: M
authors.lastname: Rzhetskaya
authors.forename: Chuansong
authors.initials: C
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: During
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Talloczy
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008474:Medial Forebrain Bundle / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D016627:Oxidopamine / Q000009:adverse effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012183:Retrograde Degeneration / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013378:Substantia Nigra / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7; D004298:Dopamine