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

• Published in: BMC neuroscience Vol. 14; no. 1; p. 6
• Main Authors: Amschl, David, Neddens, Jörg, Havas, Daniel, Flunkert, Stefanie, Rabl, Roland, Römer, Heinrich, Rockenstein, Edward, Masliah, Eliezer, Windisch, Manfred, Hutter-Paier, Birgit
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.01.2013; BioMed Central; BMC
• Subjects: Age Factors; Animals; Behavior; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation - genetics; Humans; Immunofluorescence; Intermediate Filament Proteins - genetics; Intermediate Filament Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor deficit; Mouse model; Movement Disorders - genetics; Movement Disorders - metabolism; Parkinson’s disease; Phosphorylation; Platelet-Derived Growth Factor - genetics; Synucleinopathy; Time Factors; Transgene; α-Synuclein
• ISSN: 1471-2202; 1471-2202
• DOI: 10.1186/1471-2202-14-6

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. 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. 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.