PMID- 23145024
OWN - NLM
STAT- MEDLINE
DCOM- 20130724
LR  - 20240313
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 11
DP  - 2012
TI  - Pgc-1alpha overexpression downregulates Pitx3 and increases susceptibility to MPTP 
      toxicity associated with decreased Bdnf.
PG  - e48925
LID - 10.1371/journal.pone.0048925 [doi]
LID - e48925
AB  - Multiple mechanisms likely contribute to neuronal death in Parkinson's disease 
      (PD), including mitochondrial dysfunction and oxidative stress. Peroxisome 
      proliferator-activated receptor gamma co-activator-1 alpha (PGC-1alpha) positively 
      regulates the expression of genes required for mitochondrial biogenesis and the 
      cell's antioxidant responses. Also, expression of PGC-1alpha-regulated genes is low 
      in substantia nigra (SN) neurons in early PD. Thus upregulation of PGC-1alpha is a 
      candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV) 
      was used to induce unilateral overexpression of Pgc-1alpha, or a control gene, in the 
      SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were 
      treated with saline or MPTP. Overexpression of Pgc-1alpha in the SN induced 
      expression of target genes, but unexpectedly it also greatly reduced the 
      expression of tyrosine hydroxylase (Th) and other markers of the dopaminergic 
      phenotype with resultant severe loss of striatal dopamine. Reduced Th expression 
      was associated with loss of Pitx3, a transcription factor that is critical for 
      the development and maintenance of dopaminergic cells. Expression of the 
      neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was 
      reduced. Overexpression of Pgc-1alpha also led to increased sensitivity to 
      MPTP-induced death of Th+ neurons. Pgc-1alpha overexpression alone, in the absence of 
      MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic 
      terminals. These data demonstrate that overexpression of Pgc-1alpha results in 
      dopamine depletion associated with lower levels of Pitx3 and enhances 
      susceptibility to MPTP. These data may have ramifications for neuroprotective 
      strategies targeting overexpression of PGC-1alpha in PD.
FAU - Clark, Joanne
AU  - Clark J
AD  - Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, USA. jclark3@bidmc.harvard.edu
FAU - Silvaggi, Jessica M
AU  - Silvaggi JM
FAU - Kiselak, Tomas
AU  - Kiselak T
FAU - Zheng, Kangni
AU  - Zheng K
FAU - Clore, Elizabeth L
AU  - Clore EL
FAU - Dai, Ying
AU  - Dai Y
FAU - Bass, Caroline E
AU  - Bass CE
FAU - Simon, David K
AU  - Simon DK
LA  - eng
GR  - F32 DK075253/DK/NIDDK NIH HHS/United States
GR  - K01 DA024763/DA/NIDA NIH HHS/United States
GR  - F32DK075253-02/DK/NIDDK NIH HHS/United States
GR  - K01DA024763/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121107
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (homeobox protein PITX3)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*administration & dosage
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Cell Death/drug effects/genetics
MH  - Dependovirus/metabolism
MH  - Dopamine/pharmacology
MH  - Dopaminergic Neurons/drug effects/metabolism
MH  - Down-Regulation
MH  - Homeodomain Proteins/*genetics/metabolism
MH  - MPTP Poisoning/*genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/drug effects/genetics/metabolism
MH  - Neurons/metabolism
MH  - Oxidative Stress/drug effects/genetics
MH  - Parkinson Disease/genetics/metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Substantia Nigra/drug effects/metabolism
MH  - Trans-Activators/biosynthesis/*genetics/metabolism
MH  - Transcription Factors/*genetics/metabolism
MH  - Tyrosine 3-Monooxygenase/genetics/metabolism
PMC - PMC3492133
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/11/13 06:00
MHDA- 2013/07/25 06:00
PMCR- 2012/11/07
CRDT- 2012/11/13 06:00
PHST- 2012/06/29 00:00 [received]
PHST- 2012/10/02 00:00 [accepted]
PHST- 2012/11/13 06:00 [entrez]
PHST- 2012/11/13 06:00 [pubmed]
PHST- 2013/07/25 06:00 [medline]
PHST- 2012/11/07 00:00 [pmc-release]
AID - PONE-D-12-19151 [pii]
AID - 10.1371/journal.pone.0048925 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(11):e48925. doi: 10.1371/journal.pone.0048925. Epub 2012 Nov 7.