PMID- 21307249
OWN - NLM
STAT- MEDLINE
DCOM- 20110325
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 31
IP  - 6
DP  - 2011 Feb 9
TI  - Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of 
      macroautophagy.
PG  - 2125-35
LID - 10.1523/JNEUROSCI.5519-10.2011 [doi]
AB  - 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.
FAU - Cheng, Hsiao-Chun
AU  - Cheng HC
AD  - Departments of Neurology and Pathology and Cell Biology, Columbia University, New 
      York, New York 10032, USA.
FAU - Kim, Sang Ryong
AU  - Kim SR
FAU - Oo, Tinmarla F
AU  - Oo TF
FAU - Kareva, Tatyana
AU  - Kareva T
FAU - Yarygina, Olga
AU  - Yarygina O
FAU - Rzhetskaya, Margarita
AU  - Rzhetskaya M
FAU - Wang, Chuansong
AU  - Wang C
FAU - During, Matthew
AU  - During M
FAU - Talloczy, Zsolt
AU  - Talloczy Z
FAU - Tanaka, Keiji
AU  - Tanaka K
FAU - Komatsu, Masaaki
AU  - Komatsu M
FAU - Kobayashi, Kazuto
AU  - Kobayashi K
FAU - Okano, Hideyuki
AU  - Okano H
FAU - Kholodilov, Nikolai
AU  - Kholodilov N
FAU - Burke, Robert E
AU  - Burke RE
LA  - eng
GR  - P50 NS038370-11/NS/NINDS NIH HHS/United States
GR  - R56 NS026836/NS/NINDS NIH HHS/United States
GR  - P50 NS038370/NS/NINDS NIH HHS/United States
GR  - P50 NS038370-08/NS/NINDS NIH HHS/United States
GR  - NS38370/NS/NINDS NIH HHS/United States
GR  - P50 NS038370-09/NS/NINDS NIH HHS/United States
GR  - R01 NS026836-19/NS/NINDS NIH HHS/United States
GR  - R01 NS026836/NS/NINDS NIH HHS/United States
GR  - P50 NS038370-07/NS/NINDS NIH HHS/United States
GR  - NS26836/NS/NINDS NIH HHS/United States
GR  - R01 NS026836-18/NS/NINDS NIH HHS/United States
GR  - R01 NS026836-16A1/NS/NINDS NIH HHS/United States
GR  - R01 NS026836-17/NS/NINDS NIH HHS/United States
GR  - R01 NS026836-20/NS/NINDS NIH HHS/United States
GR  - P50 NS038370-10/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Atg7 protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 6.2.1.45 (Autophagy-Related Protein 7)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Autophagy/drug effects/*physiology
MH  - Autophagy-Related Protein 7
MH  - Axons/drug effects/*metabolism/ultrastructure
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Dopamine/*metabolism
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Green Fluorescent Proteins/genetics
MH  - Medial Forebrain Bundle/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Confocal
MH  - Microscopy, Electron, Transmission/methods
MH  - Microtubule-Associated Proteins/metabolism
MH  - Neurons/*pathology
MH  - Oxidopamine/adverse effects
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - Retrograde Degeneration/etiology/*metabolism/*pathology
MH  - Signal Transduction/drug effects/genetics
MH  - Substantia Nigra/pathology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tyrosine 3-Monooxygenase/metabolism
PMC - PMC3075005
MID - NIHMS271061
EDAT- 2011/02/11 06:00
MHDA- 2011/03/26 06:00
PMCR- 2011/08/09
CRDT- 2011/02/11 06:00
PHST- 2011/02/11 06:00 [entrez]
PHST- 2011/02/11 06:00 [pubmed]
PHST- 2011/03/26 06:00 [medline]
PHST- 2011/08/09 00:00 [pmc-release]
AID - 31/6/2125 [pii]
AID - 3670489 [pii]
AID - 10.1523/JNEUROSCI.5519-10.2011 [doi]
PST - ppublish
SO  - J Neurosci. 2011 Feb 9;31(6):2125-35. doi: 10.1523/JNEUROSCI.5519-10.2011.