Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice

• Published in: Neurogenetics 2010-02, Vol.11 (1), p.107-120
• Main Authors: Nuber, Silke, Franck, Thomas, Wolburg, Hartwig, Schumann, Ulrike, Casadei, Nicolas, Fischer, Kristina, Calaminus, Carsten, Pichler, Bernd J., Chanarat, Sittinan, Teismann, Peter, Schulz, Jörg B., Luft, Andreas R., Tomiuk, Jürgen, Wilbertz, Johannes, Bornemann, Antje, Krüger, Rejko, Riess, Olaf
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain - pathology; Carrier Proteins - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Fundamental and applied biological sciences. Psychology; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; Immunohistochemistry - methods; Male; Medical sciences; Mice; Mice, Transgenic; Microscopy, Electron - methods; Models, Genetic; Molecular and cellular biology; Molecular Medicine; Nerve Tissue Proteins - genetics; Neurology; Neurosciences; Neurotransmitter Agents - metabolism; Neurotransmitters; Original Article; Parkinson's disease; Positron-Emission Tomography - methods; Prions; Proteins; Purkinje Cells - metabolism; Transgenes; Transgenic animals; Vertebrates: nervous system and sense organs
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-009-0212-2

Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson’s disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death.