Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model.
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.
Smith
Wanli W
WW
Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Liu
Zhaohui
Z
Liang
Yideng
Y
Masuda
Naoki
N
Swing
Debbie A
DA
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Troncoso
Juan C
JC
Pletnikov
Mikhail
M
Dawson
Ted M
TM
Martin
Lee J
LJ
Moran
Timothy H
TH
Lee
Michael K
MK
Borchelt
David R
DR
Ross
Christopher A
CA
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*
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