PMID- 22131425
OWN - NLM
STAT- MEDLINE
DCOM- 20120209
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 31
IP  - 48
DP  - 2011 Nov 30
TI  - Striatal dysfunctions associated with mitochondrial DNA damage in dopaminergic 
      neurons in a mouse model of Parkinson's disease.
PG  - 17649-58
LID - 10.1523/JNEUROSCI.4871-11.2011 [doi]
AB  - Parkinson's disease (PD) is one of the most common progressive neurodegenerative 
      disorders, characterized by resting tremor, rigidity, bradykinesia, and postural 
      instability. These symptoms are associated with massive loss of tyrosine 
      hydroxylase-positive neurons in the substantia nigra (SN) causing an estimated 
      70-80% depletion of dopamine (DA) in the striatum, where their projections are 
      located. Although the etiology of PD is unknown, mitochondrial dysfunctions have 
      been associated with the disease pathophysiology. We used a mouse model 
      expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI, to 
      damage mitochondrial DNA (mtDNA) in dopaminergic neurons. The expression of 
      mito-PstI induces double-strand breaks in the mtDNA, leading to an oxidative 
      phosphorylation deficiency, mostly due to mtDNA depletion. Taking advantage of a 
      dopamine transporter (DAT) promoter-driven tetracycline transactivator protein 
      (tTA), we expressed mito-PstI exclusively in dopaminergic neurons, creating a 
      novel PD transgenic mouse model (PD-mito-PstI mouse). These mice recapitulate 
      most of the major features of PD: they have a motor phenotype that is reversible 
      with l-DOPA treatment, a progressive neurodegeneration of the SN dopaminergic 
      population, and striatal DA depletion. Our results also showed that behavioral 
      phenotypes in PD-mito-PstI mice were associated with striatal dysfunctions 
      preceding SN loss of tyrosine hydroxylase-positive neurons and that other 
      neurotransmitter systems [noradrenaline (NE) and serotonin (5-HT)] were increased 
      after the disruption of DA neurons, potentially as a compensatory mechanism. This 
      transgenic mouse model provides a novel model to study the role of mitochondrial 
      defects in the axonal projections of the striatum in the pathophysiology of PD.
FAU - Pickrell, Alicia M
AU  - Pickrell AM
AD  - Neuroscience Graduate Program, Miller School of Medicine, University of Miami, 
      Miami, Florida 33136, USA.
FAU - Pinto, Milena
AU  - Pinto M
FAU - Hida, Aline
AU  - Hida A
FAU - Moraes, Carlos T
AU  - Moraes CT
LA  - eng
GR  - 5R01EY010804/EY/NEI NIH HHS/United States
GR  - 5T32NS007492/NS/NINDS NIH HHS/United States
GR  - T32 NS007459/NS/NINDS NIH HHS/United States
GR  - 5T32NS007459/NS/NINDS NIH HHS/United States
GR  - R01 EY010804/EY/NEI NIH HHS/United States
GR  - 1R01AG036871/AG/NIA NIH HHS/United States
GR  - T32 NS007492/NS/NINDS NIH HHS/United States
GR  - R01 AG036871/AG/NIA 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 (DNA, Mitochondrial)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Cell Count
MH  - Corpus Striatum/*metabolism
MH  - *DNA Damage
MH  - DNA, Mitochondrial/genetics/*metabolism
MH  - Disease Models, Animal
MH  - Dopamine/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurons/*metabolism
MH  - Parkinson Disease/genetics/*metabolism
PMC - PMC3361134
MID - NIHMS372691
EDAT- 2011/12/02 06:00
MHDA- 2012/02/10 06:00
PMCR- 2012/05/30
CRDT- 2011/12/02 06:00
PHST- 2011/12/02 06:00 [entrez]
PHST- 2011/12/02 06:00 [pubmed]
PHST- 2012/02/10 06:00 [medline]
PHST- 2012/05/30 00:00 [pmc-release]
AID - 31/48/17649 [pii]
AID - 3741207 [pii]
AID - 10.1523/JNEUROSCI.4871-11.2011 [doi]
PST - ppublish
SO  - J Neurosci. 2011 Nov 30;31(48):17649-58. doi: 10.1523/JNEUROSCI.4871-11.2011.