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

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.