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Open Access Highly Accessed Research article

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

David Amschl1, Jörg Neddens1, Daniel Havas1, Stefanie Flunkert1, Roland Rabl1, Heinrich Römer2, Edward Rockenstein3, Eliezer Masliah3, Manfred Windisch1 and Birgit Hutter-Paier1*

Author Affiliations

1 QPS Austria GmbH, Parkring 12, Grambach, 8074, Austria

2 Karl Franzens University, Institute of Zoology, Graz, 8010, Austria

3 Department of Pathology, University of California San Diego, La Jolla, CA, USA

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BMC Neuroscience 2013, 14:6  doi:10.1186/1471-2202-14-6

Published: 9 January 2013

Abstract

Background

Progressive accumulation of α-synuclein (α-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. α-Syn transgenic mouse models have been developed to investigate the effects of α-Syn accumulation on behavioral deficits and neuropathology. However, the onset and progression of pathology in α-Syn transgenic mice have not been fully characterized. For this purpose we investigated the time course of behavioral deficits and neuropathology in PDGF-β human wild type α-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 α-Syn in different brain areas. Human α-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 α-Syn confined to nuclei and perinuclear cytoplasm. Analyses of the phenotype of α-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 α-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-β α-Syn transgenic mouse model presents with early and progressive accumulation of human α-Syn that is accompanied by motor deficits. This information is essential for the design of therapeutical studies of synucleinopathies.

Keywords:
Behavior; Immunofluorescence; Motor deficit; Mouse model; Parkinson’s disease; Phosphorylation; Synucleinopathy; α-Synuclein; Transgene