PMID- 17005863
OWN - NLM
STAT- MEDLINE
DCOM- 20061127
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 26
IP  - 39
DP  - 2006 Sep 27
TI  - RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates 
      death in cellular models of Parkinson's disease by a mechanism involving 
      mammalian target of rapamycin inactivation.
PG  - 9996-10005
AB  - The molecules underlying neuron loss in Parkinson's disease (PD) are essentially 
      unknown, and current therapies focus on diminishing symptoms rather than 
      preventing neuron death. We identified RTP801 as a gene whose transcripts were 
      highly induced in a cellular model of PD in which death of neuronal 
      catecholaminergic PC12 cells was triggered by the PD mimetic 6-OHDA. Here, we 
      find that RTP801 protein is also induced in this and additional cellular and 
      animal PD models. To assess the relevance of these observations to PD, we used 
      immunohistochemistry to compare RTP801 expression in postmortem brains from PD 
      and control patients. For all PD brains examined, expression was highly elevated 
      within neuromelanin-containing neurons of the substantia nigra but not in 
      cerebellar neurons. Evaluation of the potential role of RTP801 induction in our 
      cellular model revealed that RTP801 overexpression is sufficient to promote death 
      but does not further elevate death caused by 6-OHDA. Furthermore, RTP801 
      induction is requisite for death in our cellular PD models and in 6-OHDA-treated 
      cultured sympathetic neurons in that its knockdown by short hairpin RNAs (shRNAs) 
      is protective. The mechanism by which 6-OHDA and RTP801 induce neuron death 
      appears to involve repression of mammalian target of rapamycin (mTOR) kinase 
      activity, and such death is inhibited by shRNAs targeting TSC2 (tuberous 
      sclerosis complex), a protein with which RTP801 interacts to block mTOR 
      activation. Our findings thus suggest that the elevation of RTP801 we detect in 
      PD substantia nigral neurons may mediate their degeneration and death and that 
      RTP801 and its signaling cascade may be novel potential therapeutic targets for 
      the disease.
FAU - Malagelada, Cristina
AU  - Malagelada C
AD  - Department of Pathology and Center for Neurobiology and Behavior, Columbia 
      University, New York, New York 10032, USA. cm2273@columbia.edu
FAU - Ryu, Elizabeth J
AU  - Ryu EJ
FAU - Biswas, Subhas C
AU  - Biswas SC
FAU - Jackson-Lewis, Vernice
AU  - Jackson-Lewis V
FAU - Greene, Lloyd A
AU  - Greene LA
LA  - eng
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 (Adaptor Proteins, Signal Transducing)
RN  - 0 (DDIT4 protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Ddit4 protein, rat)
RN  - 0 (Ddit4l protein, mouse)
RN  - 0 (Melanins)
RN  - 0 (Repressor Proteins)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (neuromelanin)
RN  - 03L9OT429T (Rotenone)
RN  - 11089-65-9 (Tunicamycin)
RN  - 63231-63-0 (RNA)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Camptothecin/pharmacology
MH  - DNA-Binding Proteins/antagonists & inhibitors/genetics/*physiology
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - MPTP Poisoning/metabolism/pathology
MH  - Male
MH  - Melanins/analysis
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nerve Growth Factor/physiology
MH  - Neurons/drug effects/metabolism
MH  - Oxidopamine/pharmacology/toxicity
MH  - PC12 Cells
MH  - Parkinsonian Disorders/*metabolism/pathology
MH  - Phosphorylation
MH  - Protein Kinases/*physiology
MH  - Protein Processing, Post-Translational
MH  - RNA/genetics/pharmacology
MH  - RNA Interference
MH  - Rats
MH  - Repressor Proteins
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Rotenone/pharmacology
MH  - Signal Transduction/drug effects
MH  - Substantia Nigra/*metabolism/pathology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/analysis/genetics/*physiology
MH  - Transcription, Genetic/drug effects
MH  - Transfection
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/physiology
MH  - Tunicamycin/pharmacology
PMC - PMC6674487
EDAT- 2006/09/29 09:00
MHDA- 2006/12/09 09:00
PMCR- 2007/03/27
CRDT- 2006/09/29 09:00
PHST- 2006/09/29 09:00 [pubmed]
PHST- 2006/12/09 09:00 [medline]
PHST- 2006/09/29 09:00 [entrez]
PHST- 2007/03/27 00:00 [pmc-release]
AID - 26/39/9996 [pii]
AID - 3150945 [pii]
AID - 10.1523/JNEUROSCI.3292-06.2006 [doi]
PST - ppublish
SO  - J Neurosci. 2006 Sep 27;26(39):9996-10005. doi: 10.1523/JNEUROSCI.3292-06.2006.