Transgenic mice expressing S129 phosphorylation mutations in α-synuclein

Aggregated alpha-synuclein is a predominant constituent of Lewy bodies, the intracellular protein aggregates seen in Parkinson's disease. While most alpha-synuclein in the nervous system is unphosphorylated, the majority of alpha-synuclein in Lewy bodies is phosphorylated at serine 129 (S129). We developed transgenic mice expressing human SNCA with either a phosphomimic (S129D) or a non-phosphorylatable (S129A) mutation, on a mouse Snca knockout background. Transgenic lines with each mutation expressing the human alpha-synuclein protein at levels ranging from 0.3 to 1.9 fold of endogenous mouse protein were chosen to avoid toxic overexpression effects. We previously demonstrated an altered distribution of presynaptic vesicles in Snca knockout mice, as well as enhanced interaction between presynaptic cytoskeletal proteins and alpha-synuclein when phosphorylated at S129 or carrying an S129D mutation. We therefore examined alpha-synuclein's synaptic localization and the distribution of presynaptic vesicles in these mutants. In addition, we evaluated the transgenic lines for reduced colonic motility, an early marker of alpha-synuclein pathology, and alpha-synuclein aggregates. No abnormalities were detected in mice expressing either phosphorylation mutant protein as their only alpha-synuclein protein. These results suggest the S129A and S129D mutations have no obvious effect on alpha-synuclein function. (C) 2014 Elsevier Ireland Ltd. All rights reserved.