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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/109661
- author
- Lotharius, Julie
LU
; Barg, Sebastian
LU
; Wiekop, Pia
; Lundberg, Cecilia
LU
; Raymon, Heather K.
and Brundin, Patrik
LU
- organization
- publishing date
- 2002
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 277
- issue
- 41
- pages
- 38884 - 38894
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000178529600111
- scopus:0037064078
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M205518200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041), Islet cell physiology (013212142)
- 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
- 2016-04-01 11:45:46
- date last changed
- 2022-04-20 21:25:13
@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 = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line.}},
url = {{https://lup.lub.lu.se/search/files/2630377/623637.pdf}},
doi = {{10.1074/jbc.M205518200}},
volume = {{277}},
year = {{2002}},
}