Synphilin-1 attenuates neuronal degeneration in the A53T α-synuclein transgenic mouse model

WW Smith, Z Liu, Y Liang, N Masuda… - Human molecular …, 2010 - academic.oup.com
WW Smith, Z Liu, Y Liang, N Masuda, DA Swing, NA Jenkins, NG Copeland, JC Troncoso
Human molecular genetics, 2010academic.oup.com
Genetic alterations in α-synuclein cause autosomal dominant familial Parkinsonism and may
contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an α-synuclein-interacting
protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in
vivo role of synphilin-1 in α-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 α-synuclein double-transgenic mice …
Abstract
Genetic alterations in α-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an α-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in α-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 α-synuclein double-transgenic mice survived longer than A53T α-synuclein single-transgenic mice. There were attenuated A53T α-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 α-synucleinopathy and play a neuroprotective role against A53T α-synuclein toxicity in vivo.
Oxford University Press