Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice.
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.
Nuber
Silke
S
Department of Medical Genetics, University of Tübingen, Calwerstr. 7, 72076 Tübingen, Germany.
Franck
Thomas
T
Wolburg
Hartwig
H
Schumann
Ulrike
U
Casadei
Nicolas
N
Fischer
Kristina
K
Calaminus
Carsten
C
Pichler
Bernd J
BJ
Chanarat
Sittinan
S
Teismann
Peter
P
Schulz
Jörg B
JB
Luft
Andreas R
AR
Tomiuk
Jürgen
J
Wilbertz
Johannes
J
Bornemann
Antje
A
Krüger
Rejko
R
Riess
Olaf
O
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*
D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C118958:SNCAIP protein, human; D051844:alpha-Synuclein