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A Genetic Mouse Model of Parkinson's Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine

Brehm, N.; Bez, Francesco LU ; Carlsson, T.; Kern, B.; Gispert, S.; Auburger, G. and Cenci Nilsson, Angela LU (2015) In Molecular Neurobiology 52(3). p.1152-1164
Abstract
Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (l-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven... (More)
Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (l-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alpha-synuclein, Mouse model, Parkinson's disease, Synaptic plasticity
in
Molecular Neurobiology
volume
52
issue
3
pages
1152 - 1164
publisher
Humana Press
external identifiers
  • wos:000361903400007
  • scopus:84942828573
ISSN
1559-1182
DOI
10.1007/s12035-014-8911-6
language
English
LU publication?
yes
id
80208a6c-a5ee-42a9-bfee-d590ab32e956 (old id 8058420)
date added to LUP
2015-11-19 10:34:33
date last changed
2017-06-11 04:03:05
@article{80208a6c-a5ee-42a9-bfee-d590ab32e956,
  abstract     = {Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (l-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.},
  author       = {Brehm, N. and Bez, Francesco and Carlsson, T. and Kern, B. and Gispert, S. and Auburger, G. and Cenci Nilsson, Angela},
  issn         = {1559-1182},
  keyword      = {Alpha-synuclein,Mouse model,Parkinson's disease,Synaptic plasticity},
  language     = {eng},
  number       = {3},
  pages        = {1152--1164},
  publisher    = {Humana Press},
  series       = {Molecular Neurobiology},
  title        = {A Genetic Mouse Model of Parkinson's Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine},
  url          = {http://dx.doi.org/10.1007/s12035-014-8911-6},
  volume       = {52},
  year         = {2015},
}