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

Wanli W. Smith, Zhaohui Liu, Yideng Liang, Naoki Masuda, Debbie A. Swing, Nancy A. Jenkins, Neal G. Copeland, Juan C. Troncoso, Mikhail Pletnikov, Ted M. Dawson, Lee J. Martin, Timothy H. Moran, Michael K. Lee, David R. Borchelt, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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-synucleinlinked 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.

Original languageEnglish (US)
Article numberddq086
Pages (from-to)2087-2098
Number of pages12
JournalHuman molecular genetics
Issue number11
StatePublished - Feb 25 2010

Bibliographical note

Funding Information:
This work is supported by NIH grant NS38377 and RO1NS055252.


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