PMID- 24920625
OWN - NLM
STAT- MEDLINE
DCOM- 20140804
LR  - 20231012
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 34
IP  - 24
DP  - 2014 Jun 11
TI  - Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a 
      study in isolated synaptic vesicles of human and nonhuman primate striatum.
PG  - 8210-8
LID - 10.1523/JNEUROSCI.5456-13.2014 [doi]
AB  - The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic 
      Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely 
      confined to synaptic vesicles where it is protected from metabolic breakdown. In 
      the cytoplasm, however, free DA can give rise to formation of cytotoxic free 
      radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by 
      continuous pumping activity of the vesicular monoamine transporter (VMAT)2. 
      Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy 
      radicals ultimately resulting in degeneration of DAergic neurons. Here, we 
      isolated for the first time, DA storage vesicles from the striatum of six 
      autopsied brains of PD patients and four controls and measured several indices of 
      vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and 
      binding of the VMAT2-selective label [(3)H]dihydrotetrabenazine were profoundly 
      reduced in PD by 87-90% and 71-80%, respectively; (2) after correcting for DA 
      nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced 
      in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport 
      defect appeared specific for PD as it was not present in Macaca fascicularis (7 
      MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal 
      neurodegeneration; and (4) DA efflux studies and measurements of acidification in 
      the vesicular preparations suggest that the DA storage impairment was localized 
      at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early 
      abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.
CI  - Copyright (c) 2014 the authors 0270-6474/14/348210-09$15.00/0.
FAU - Pifl, Christian
AU  - Pifl C
AD  - Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, 
      christian.pifl@meduniwien.ac.at.
FAU - Rajput, Alex
AU  - Rajput A
AD  - Movement Disorders Program Saskatchewan, Royal University Hospital, University of 
      Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.
FAU - Reither, Harald
AU  - Reither H
AD  - Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
FAU - Blesa, Javier
AU  - Blesa J
AUID- ORCID: 0000-0002-4257-1325
AD  - Movement Disorders Group, Neurosciences Division, CIMA, and Department of 
      Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, 
      Spain, and.
FAU - Cavada, Carmen
AU  - Cavada C
AD  - Departamento de Anatomia, Histologia y Neurociencia, Facultad de Medicina, 
      Universidad Autonoma de Madrid, E28049 Madrid, Spain.
FAU - Obeso, Jose A
AU  - Obeso JA
AD  - Movement Disorders Group, Neurosciences Division, CIMA, and Department of 
      Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, 
      Spain, and.
FAU - Rajput, Ali H
AU  - Rajput AH
AD  - Movement Disorders Program Saskatchewan, Royal University Hospital, University of 
      Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.
FAU - Hornykiewicz, Oleh
AU  - Hornykiewicz O
AD  - Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Dopamine Uptake Inhibitors)
RN  - 0 (Slc18a2 protein, mouse)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 10028-17-8 (Tritium)
RN  - 3466-75-9 (dihydrotetrabenazine)
RN  - VTD58H1Z2X (Dopamine)
RN  - X77S6GMS36 (Homovanillic Acid)
RN  - Z9O08YRN8O (Tetrabenazine)
SB  - IM
EIN - J Neurosci. 2015 Nov 25;35(47):15767
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Corpus Striatum/pathology/*ultrastructure
MH  - Disease Models, Animal
MH  - Dopamine/*metabolism
MH  - Dopamine Uptake Inhibitors/pharmacokinetics
MH  - Female
MH  - Homovanillic Acid/metabolism
MH  - Humans
MH  - MPTP Poisoning/pathology
MH  - Macaca fascicularis
MH  - Male
MH  - Parkinson Disease/*pathology
MH  - Synaptic Vesicles/*metabolism
MH  - Tetrabenazine/analogs & derivatives/pharmacokinetics
MH  - Tritium/metabolism/pharmacokinetics
MH  - Vesicular Monoamine Transport Proteins/*metabolism
PMC - PMC6608236
OTO - NOTNLM
OT  - Parkinson's disease
OT  - VMAT2
OT  - dopamine
OT  - striatum
OT  - synaptic vesicles
EDAT- 2014/06/13 06:00
MHDA- 2014/08/05 06:00
PMCR- 2014/12/11
CRDT- 2014/06/13 06:00
PHST- 2014/06/13 06:00 [entrez]
PHST- 2014/06/13 06:00 [pubmed]
PHST- 2014/08/05 06:00 [medline]
PHST- 2014/12/11 00:00 [pmc-release]
AID - 34/24/8210 [pii]
AID - 5456-13 [pii]
AID - 10.1523/JNEUROSCI.5456-13.2014 [doi]
PST - ppublish
SO  - J Neurosci. 2014 Jun 11;34(24):8210-8. doi: 10.1523/JNEUROSCI.5456-13.2014.