Nuber S, Rajsombath M, Minakaki G, Winkler J, Müller CP, Ericsson M, Caldarone B, Dettmer U, Selkoe DJ (2018)
Publication Type: Journal article
Publication year: 2018
Book Volume: 100
Pages Range: 75-90.e5
Journal Issue: 1
DOI: 10.1016/j.neuron.2018.09.014
α-Synuclein (αS) 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 αS, α-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. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS 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 αS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications.
APA:
Nuber, S., Rajsombath, M., Minakaki, G., Winkler, J., Müller, C.P., Ericsson, M.,... Selkoe, D.J. (2018). Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease. Neuron, 100(1), 75-90.e5. https://doi.org/10.1016/j.neuron.2018.09.014
MLA:
Nuber, Silke, et al. "Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease." Neuron 100.1 (2018): 75-90.e5.
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