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

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• 作者：N. Brehm ; F. Bez ; T. Carlsson ; B. Kern ; S. Gispert ; G. Auburger…
• 关键词：Alpha ; synuclein ; Mouse model ; Parkinson’s disease ; Synaptic plasticity
• 刊名：Molecular Neurobiology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：52
• 期：3
• 页码：1152-1164
• 全文大小：1,584 KB
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• 作者单位：N. Brehm (1)
  F. Bez (2)
  T. Carlsson (3) (4)
  B. Kern (3)
  S. Gispert (1)
  G. Auburger (1)
  M. A. Cenci (2)
  
  1. Experimental Neurology, Department of Neurology, Medical School, Goethe University Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
  2. Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, SE-221 84, Lund, Sweden
  3. Institute of Neurophysiology, Neuroscience Center, Goethe University Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
  4. Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 431, SE-40530, Gothenburg, Sweden
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

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. Keywords Alpha-synuclein Mouse model Parkinson’s disease Synaptic plasticity