It has been more than a century since the first evidence linking the process of amyloid formation to the pathogenesis of Alzheimer's disease. These results suggest the S129A and S129D mutations have no obvious effect on α-synuclein function. No abnormalities were detected in mice expressing either phosphorylation mutant protein as their only α-synuclein protein. In addition, we evaluated the transgenic lines for reduced colonic motility, an early marker of α-synuclein pathology, and α-synuclein aggregates. We therefore examined α-synuclein& amp amp amp amp amp amp amp amp amp amp amp amp amp #39 s synaptic localization and the distribution of presynaptic vesicles in these mutants. We previously demonstrated an altered distribution of presynaptic vesicles in Snca knockout mice, as well as enhanced interaction between presynaptic cytoskeletal proteins and α-synuclein when phosphorylated at S129 or carrying an S129D mutation. Transgenic lines with each mutation expressing the human α-synuclein protein at levels ranging from 0.3 to 1.9 fold of endogenous mouse protein were chosen to avoid toxic overexpression effects.
We developed transgenic mice expressing human SNCA with either a phosphomimic (S129D) or a non-phosphorylatable (S129A) mutation, on a mouse Snca knockout background. While most α-synuclein in the nervous system is unphosphorylated, the majority of α-synuclein in Lewy bodies is phosphorylated at serine 129 (S129). Aggregated α-synuclein is a predominant constituent of Lewy bodies, the intracellular protein aggregates seen in Parkinson& amp amp amp amp amp amp amp amp amp amp amp amp amp #39 s disease.
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