title: Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice.
abstract: Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson 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.
authors.affiliation: Department of Medical Genetics, University of Tübingen, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Thomas
authors.initials: T
authors.lastname: Franck
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schumann
authors.forename: Nicolas
authors.initials: N
authors.lastname: Casadei
authors.forename: Kristina
authors.initials: K
authors.lastname: Fischer
authors.forename: Carsten
authors.initials: C
authors.lastname: Calaminus
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Sittinan
authors.initials: S
authors.lastname: Chanarat
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Luft
authors.forename: Jürgen
authors.initials: J
authors.lastname: Tomiuk
authors.forename: Johannes
authors.initials: J
authors.lastname: Wilbertz
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron / Q000379:methods; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018377:Neurotransmitter Agents / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011689:Purkinje Cells / Q000378:metabolism*; D019076:Transgenes; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C118958:SNCAIP protein, human; D051844:alpha-Synuclein