title: Aggregate formation and toxicity by wild-type and R621C synphilin-1 in the nigrostriatal system of mice using adenoviral vectors.
abstract: Synphilin-1 was described as a protein interacting with alpha-synuclein and is commonly found in Lewy bodies, the pathological hallmark of Parkinson's disease (PD). Our group has previously described and characterized in vitro a mutation in the synphilin-1 gene (R621C) in PD patients. Providing the first characterization of synphilin-1 expression in an animal model, we here used adenoviral gene transfer to study the effects of wild-type (WT) and R621C synphilin-1 in dopaminergic neurons in mouse brain. As synphilin-1 is commonly used to trigger aggregation of alpha-synuclein in cell culture, we investigated not only non-transgenic C57Bl/6 mice but also A30P-alpha-synuclein transgenic animals. Both WT synphilin-1 and R621C synphilin-1 led to the formation of Thioflavine-S positive inclusions in C57Bl/6 mice and degeneration of dopaminergic neurons in the substantia nigra. R621C synphilin-1 induced more aggregate formation than WT synphilin-1 in A30P-alpha-synuclein transgenic mice, consistent with the role of the R621C mutation as a susceptibility factor for PD. Synphilin-1 expression may be used to improve current mouse models of PD, as it induced both the formation of aggregates and degeneration of dopaminergic neurons, two core characteristics of PD that have not been well reproduced with expression of alpha-synuclein.
authors.affiliation: Department of Neurodegeneration and Restorative Research, DFG Research Center for Molecular Physiology of Brain and Center for Neurological Medicine, University of Göttingen, Göttingen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Krenz
authors.forename: Björn H
authors.initials: BH
authors.lastname: Falkenburger
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.forename: Anja
authors.initials: A
authors.lastname: Drinkut
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000235:genetics*; D052160:Benzothiazoles; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000139:chemically induced*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C498464:Sncaip protein, mouse; D013844:Thiazoles; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C009462:thioflavin T; D001120:Arginine; D014446:Tyrosine 3-Monooxygenase; D003545:Cysteine