| First Author | Nuber S | Year | 2018 |
| Journal | Neuron | Volume | 100 |
| Issue | 1 | Pages | 75-90.e5 |
| PubMed ID | 30308173 | Mgi Jnum | J:268903 |
| Mgi Id | MGI:6269335 | Doi | 10.1016/j.neuron.2018.09.014 |
| Citation | Nuber S, et al. (2018) Abrogating Native alpha-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease. Neuron 100(1):75-90.e5 |
| abstractText | alpha-Synuclein (alphaS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of alphaS, alpha-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E-->K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. alphaS monomers accumulate at membranes and form vesicle-rich inclusions. alphaS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal alphaS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications. |
