Overexpression of synphilin-1 promotes clearance of soluble and misfolded alpha-synuclein without restoring the motor phenotype in aged A30P transgenic mice

Nicolas Casadei, Anne Maria Pö hler, Cristina Tomás-Zapico, Jesús Torres-Peraza, Ivo Schwedhelm, Annemarie Witz, Irina Zamolo, Raymond De Heer, Berry Spruijt, Lucas P.J.J. Noldus, Jochen Klucken, José J. Lucas, Philipp J. Kahle, Rejko Krüger, Olaf Riess*, Silke Nuber

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)


Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures arecomposed of fibrillized and ubiquitinated alpha-synuclein suggesting that impairedprotein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation.Wetherefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable inageddouble-transgenic mice, paralleledbyanincreaseof ubiquitinatedproteinsandhigh autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagicsusceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression.

Original languageEnglish
Article numberddt467
Pages (from-to)767-781
Number of pages15
JournalHuman Molecular Genetics
Issue number3
Publication statusPublished - Feb 2014
Externally publishedYes


Dive into the research topics of 'Overexpression of synphilin-1 promotes clearance of soluble and misfolded alpha-synuclein without restoring the motor phenotype in aged A30P transgenic mice'. Together they form a unique fingerprint.

Cite this