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

Autor:	Nuber S; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Rajsombath M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Minakaki G; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU), Erlangen-Nürnberg, 91054 Erlangen, Germany., Winkler J; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU), Erlangen-Nürnberg, 91054 Erlangen, Germany., Müller CP; Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University (FAU), Erlangen-Nürnberg, 91054 Erlangen, Germany., Ericsson M; Electron Microscopy Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Caldarone B; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; NeuroBehavior Laboratory, Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA 02115, USA., Dettmer U; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Selkoe DJ; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: dselkoe@bwh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2018 Oct 10; Vol. 100 (1), pp. 75-90.e5.
DOI:	10.1016/j.neuron.2018.09.014
Abstrakt:	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. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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