title: Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model.
abstract: Genetic alterations in alpha-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an alpha-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in alpha-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of alpha-synucleinopathy and play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.
authors.affiliation: Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Liu
authors.forename: Yideng
authors.initials: Y
authors.lastname: Liang
authors.forename: Naoki
authors.initials: N
authors.lastname: Masuda
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Swing
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C498464:Sncaip protein, mouse; D051844:alpha-Synuclein; C505409:Casp3 protein, mouse; D053148:Caspase 3