Document Detail


Vesicular monoamine transporter-2 and aromatic L-amino acid decarboxylase enhance dopamine delivery after L-3, 4-dihydroxyphenylalanine administration in Parkinsonian rats.
MedLine Citation:
PMID:  10191339     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Medical therapy in Parkinson's disease (PD) is limited by the short-duration response and development of dyskinesia that result from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy. These problems occur partly because the loss of dopamine storage sites leads to erratic dopamine delivery. Vesicular monoamine transporter-2 (VMAT-2) plays a critical role in dopamine storage by packaging dopamine into synaptic vesicles and regulating sustained release of dopamine. To restore the capacity to produce and store dopamine in parkinsonian rats, primary skin fibroblast cells (PF) were genetically modified with aromatic L-amino acid decarboxylase (AADC) and VMAT-2 genes. After incubation with L-DOPA in culture, the doubly transduced fibroblast cells (PFVMAA) produced and stored dopamine at a much higher level than the cells with either gene alone. PFVMAA cells in culture released dopamine gradually in a constitutive manner. Genetically modified fibroblast cells were grafted in parkinsonian rat striata, and L-DOPA was systemically administered. Higher dopamine levels were sustained for a longer duration in rats grafted with PFVMAA cells than in those grafted with either control cells or cells with AADC alone. These findings underscore the importance of dopamine storage capacity in determining the efficacy of L-DOPA therapy and illustrate a novel method of gene therapy combined with precursor administration to overcome the major obstacles of PD treatment.
Authors:
W Y Lee; J W Chang; N L Nemeth; U J Kang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  19     ISSN:  0270-6474     ISO Abbreviation:  J. Neurosci.     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-04-27     Completed Date:  1999-04-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3266-74     Citation Subset:  IM    
Affiliation:
Department of Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aromatic-L-Amino-Acid Decarboxylases / genetics*
Dopamine / metabolism*
Dopamine Agents / therapeutic use*
Female
Fibroblasts / metabolism
Gene Therapy
Levodopa / therapeutic use*
Membrane Glycoproteins / genetics
Membrane Transport Proteins*
Neuropeptides*
Neurotransmitter Agents / genetics*
Parkinson Disease, Secondary / metabolism,  therapy*
Rats
Rats, Inbred F344
Transduction, Genetic
Vesicular Biogenic Amine Transport Proteins
Vesicular Monoamine Transport Proteins
Grant Support
ID/Acronym/Agency:
NS32080/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Dopamine Agents; 0/Levodopa; 0/Membrane Glycoproteins; 0/Membrane Transport Proteins; 0/Neuropeptides; 0/Neurotransmitter Agents; 0/Vesicular Biogenic Amine Transport Proteins; 0/Vesicular Monoamine Transport Proteins; EC 4.1.1.28/Aromatic-L-Amino-Acid Decarboxylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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