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Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line.

Lotharius, Julie LU ; Barg, Sebastian LU ; Wiekop, Pia; Lundberg, Cecilia LU ; Raymon, Heather K. and Brundin, Patrik LU (2002) In Journal of Biological Chemistry 277(41). p.38884-38894
Abstract
Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinsons disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-synuclein is a presynaptic nerve terminal protein of unknown function, though some studies suggest it is important for synapse formation and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein.... (More)
Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinsons disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-synuclein is a presynaptic nerve terminal protein of unknown function, though some studies suggest it is important for synapse formation and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in downregulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Since extra-vesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinsons disease by triggering protracted, low-grade dopamine toxicity resulting in terminal degeneration and ultimately cell death. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
277
issue
41
pages
38884 - 38894
publisher
ASBMB
external identifiers
  • wos:000178529600111
  • scopus:0037064078
ISSN
1083-351X
DOI
10.1074/jbc.M205518200
language
English
LU publication?
yes
id
53dae798-cb06-42fd-9cd7-b09df0c08643 (old id 109661)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12145295&dopt=Abstract
date added to LUP
2007-07-17 10:38:34
date last changed
2017-12-10 03:41:47
@article{53dae798-cb06-42fd-9cd7-b09df0c08643,
  abstract     = {Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinsons disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-synuclein is a presynaptic nerve terminal protein of unknown function, though some studies suggest it is important for synapse formation and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in downregulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Since extra-vesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinsons disease by triggering protracted, low-grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.},
  author       = {Lotharius, Julie and Barg, Sebastian and Wiekop, Pia and Lundberg, Cecilia and Raymon, Heather K. and Brundin, Patrik},
  issn         = {1083-351X},
  language     = {eng},
  number       = {41},
  pages        = {38884--38894},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line.},
  url          = {http://dx.doi.org/10.1074/jbc.M205518200},
  volume       = {277},
  year         = {2002},
}