Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease

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

Journal

Neuron Elsevier (Cell Press)

Book Volume: 100

Pages Range: 75-90.e5

Journal Issue: 1

DOI: 10.1016/j.neuron.2018.09.014

Abstract

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.

Authors with CRIS profile

Georgia Minakaki Professur für Molekulare Neurologie Jürgen Winkler Professur für Molekulare Neurologie Peter Christian Müller Professur für Suchtmedizin

Involved external institutions

Brigham and Women's Hospital (BWH) US United States (USA) (US) Harvard University US United States (USA) (US)

How to cite

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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