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Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons

Ulusoy, Ayse LU ; Björklund, Tomas LU ; Buck, Kerstin LU and Kirik, Deniz LU (2012) In Neurobiology of Disease 47(3). p.367-377
Abstract
Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant... (More)
Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant increase in dopaminergic neurodegeneration. Importantly, silencing the tyrosine hydroxylase enzyme - thereby reducing dopamine content in the nigral neurons - reversed the increased vulnerability back to the baseline level observed in wild-type littermates, but failed to eliminate it completely. Importantly, TH knockdown was not effective in altering the toxicity in the wild-type animals. Taken together, our data suggest that under normal circumstances, in healthy dopamine neurons, cytoplasmic dopamine is tightly controlled such that it does not contribute significantly to alpha-synuclein mediated toxicity. Dysregulation of the dopamine machinery in the substantia nigra, on the other hand, could act as a trigger for induction of increased toxicity in these neurons and could explain how these neurons become more vulnerable and die in the disease process. (C) 2012 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Short hairpin RNA, Tyrosine hydroxylase, Adeno-associated virus, VMAT2, Transgenic mice
in
Neurobiology of Disease
volume
47
issue
3
pages
367 - 377
publisher
Elsevier
external identifiers
  • wos:000306622300008
  • scopus:84862303338
ISSN
0969-9961
DOI
10.1016/j.nbd.2012.05.012
language
English
LU publication?
yes
id
503aee20-125a-4191-8640-2575d8039af8 (old id 3079792)
date added to LUP
2012-10-05 07:17:04
date last changed
2017-09-10 03:18:37
@article{503aee20-125a-4191-8640-2575d8039af8,
  abstract     = {Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant increase in dopaminergic neurodegeneration. Importantly, silencing the tyrosine hydroxylase enzyme - thereby reducing dopamine content in the nigral neurons - reversed the increased vulnerability back to the baseline level observed in wild-type littermates, but failed to eliminate it completely. Importantly, TH knockdown was not effective in altering the toxicity in the wild-type animals. Taken together, our data suggest that under normal circumstances, in healthy dopamine neurons, cytoplasmic dopamine is tightly controlled such that it does not contribute significantly to alpha-synuclein mediated toxicity. Dysregulation of the dopamine machinery in the substantia nigra, on the other hand, could act as a trigger for induction of increased toxicity in these neurons and could explain how these neurons become more vulnerable and die in the disease process. (C) 2012 Elsevier Inc. All rights reserved.},
  author       = {Ulusoy, Ayse and Björklund, Tomas and Buck, Kerstin and Kirik, Deniz},
  issn         = {0969-9961},
  keyword      = {Short hairpin RNA,Tyrosine hydroxylase,Adeno-associated virus,VMAT2,Transgenic mice},
  language     = {eng},
  number       = {3},
  pages        = {367--377},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons},
  url          = {http://dx.doi.org/10.1016/j.nbd.2012.05.012},
  volume       = {47},
  year         = {2012},
}