PMID- 22008911
OWN - NLM
STAT- MEDLINE
DCOM- 20120710
LR  - 20220309
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 20
IP  - 2
DP  - 2012 Feb
TI  - AAV transduction of dopamine neurons with constitutively active Rheb protects 
      from neurodegeneration and mediates axon regrowth.
PG  - 275-86
LID - 10.1038/mt.2011.213 [doi]
AB  - There are currently no therapies that provide either protection or restoration of 
      neuronal function for adult-onset neurodegenerative diseases such as Parkinson's 
      disease (PD). Many clinical efforts to provide such benefits by infusion of 
      neurotrophic factors have failed, in spite of robust effects in preclinical 
      assessments. One important reason for these failures is the difficulty, due to 
      diffusion limits, of providing these protein molecules in sufficient amounts to 
      the intended cellular targets in the central nervous system. This challenge 
      suggests an alternative approach, that of viral vector transduction to directly 
      activate the intracellular signaling pathways that mediate neurotrophic effects. 
      To this end we have investigated the ability of a constitutively active form of 
      the GTPase Rheb, an important activator of mammalian target of rapamycin (mTor) 
      signaling, to mediate neurotrophic effects in dopamine neurons of the substantia 
      nigra (SN), a population of neurons affected in PD. We find that constitutively 
      active hRheb(S16H) induces many neurotrophic effects in mice, including abilities 
      to both preserve and restore the nigrostriatal dopaminergic axonal projections in 
      a highly destructive neurotoxin model. We conclude that direct viral vector 
      transduction of vulnerable neuronal populations to activate intracellular 
      neurotrophic signaling pathways offers promise for the treatment of 
      neurodegenerative disease.
FAU - Kim, Sang Ryong
AU  - Kim SR
AD  - Department of Neurology, Columbia University, New York, New York 10032, USA.
FAU - Kareva, Tatyana
AU  - Kareva T
FAU - Yarygina, Olga
AU  - Yarygina O
FAU - Kholodilov, Nikolai
AU  - Kholodilov N
FAU - Burke, Robert E
AU  - Burke RE
LA  - eng
GR  - R56 NS026836/NS/NINDS NIH HHS/United States
GR  - P50 NS038370/NS/NINDS NIH HHS/United States
GR  - NS38370/NS/NINDS NIH HHS/United States
GR  - R01 NS026836/NS/NINDS NIH HHS/United States
GR  - NS26836/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111018
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Neuropeptides)
RN  - 0 (Phosphoproteins)
RN  - 0 (RHEB protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Axons/drug effects/*metabolism
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins
MH  - Corpus Striatum/drug effects/metabolism
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Dopaminergic Neurons/*metabolism
MH  - Eukaryotic Initiation Factors
MH  - Genetic Therapy
MH  - Genetic Vectors/administration & dosage/*genetics
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Monomeric GTP-Binding Proteins/*genetics/metabolism
MH  - Neuropeptides/*genetics/metabolism
MH  - Oxidopamine/adverse effects
MH  - Parkinson Disease/*prevention & control/therapy
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Ras Homolog Enriched in Brain Protein
MH  - Signal Transduction
MH  - Substantia Nigra/drug effects/metabolism
MH  - *Transduction, Genetic
PMC - PMC3277224
EDAT- 2011/10/20 06:00
MHDA- 2012/07/11 06:00
PMCR- 2013/02/01
CRDT- 2011/10/20 06:00
PHST- 2011/10/20 06:00 [entrez]
PHST- 2011/10/20 06:00 [pubmed]
PHST- 2012/07/11 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - S1525-0016(16)30479-8 [pii]
AID - 10.1038/mt.2011.213 [doi]
PST - ppublish
SO  - Mol Ther. 2012 Feb;20(2):275-86. doi: 10.1038/mt.2011.213. Epub 2011 Oct 18.