Time course and progression of wild type α-Synuclein accumulation in a transgenic mouse model

被引:33
作者
Amschl, David [1 ]
Neddens, Joerg [1 ]
Havas, Daniel [1 ]
Flunkert, Stefanie [1 ]
Rabl, Roland [1 ]
Roemer, Heinrich [2 ]
Rockenstein, Edward [3 ]
Masliah, Eliezer [3 ]
Windisch, Manfred [1 ]
Hutter-Paier, Birgit [1 ]
机构
[1] QPS Austria GmbH, A-8074 Grambach, Austria
[2] Karl Franzens Univ Graz, Inst Zool, A-8010 Graz, Austria
[3] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
关键词
Behavior; Immunofluorescence; Motor deficit; Mouse model; Parkinson's disease; Phosphorylation; Synucleinopathy; alpha-Synuclein; Transgene; FAMILIAL PARKINSONS-DISEASE; MULTIPLE SYSTEM ATROPHY; LEWY BODY DISEASE; AUTOPHAGY PATHWAY; GROWTH-FACTOR; B-CHAIN; MICE; EXPRESSION; ERBB4; ADULT;
D O I
10.1186/1471-2202-14-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: Progressive accumulation of alpha-synuclein (alpha-Syn) protein in different brain regions is a hallmark of synucleinopathic diseases, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. alpha-Syn transgenic mouse models have been developed to investigate the effects of alpha-Syn accumulation on behavioral deficits and neuropathology. However, the onset and progression of pathology in alpha-Syn transgenic mice have not been fully characterized. For this purpose we investigated the time course of behavioral deficits and neuropathology in PDGF-beta human wild type alpha-Syn transgenic mice (D-Line) between 3 and 12 months of age. Results: These mice showed progressive impairment of motor coordination of the limbs that resulted in significant differences compared to non-transgenic littermates at 9 and 12 months of age. Biochemical and immunohistological analyses revealed constantly increasing levels of human alpha-Syn in different brain areas. Human alpha-Syn was expressed particularly in somata and neurites of a subset of neocortical and limbic system neurons. Most of these neurons showed immunoreactivity for phosphorylated human alpha-Syn confined to nuclei and perinuclear cytoplasm. Analyses of the phenotype of alpha-Syn expressing cells revealed strong expression in dopaminergic olfactory bulb neurons, subsets of GABAergic interneurons and glutamatergic principal cells throughout the telencephalon. We also found human alpha-Syn expression in immature neurons of both the ventricular zone and the rostral migratory stream, but not in the dentate gyrus. Conclusion: The present study demonstrates that the PDGF-beta alpha-Syn transgenic mouse model presents with early and progressive accumulation of human alpha-Syn that is accompanied by motor deficits. This information is essential for the design of therapeutical studies of synucleinopathies.
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页数:14
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