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

Neuron. 2018 Oct 10;100(1):75-90.e5. 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.

Keywords: L-DOPA; Parkinson’s disease; alpha-synuclein; dementia with Lewy bodies; monomer; mouse-model; neurodegeneration; tetramer; transgenic; tremor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Brain / pathology
  • Disease Models, Animal
  • Levodopa / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation, Missense
  • Neurons / pathology
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / pathology
  • Protein Conformation
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics*


  • Antiparkinson Agents
  • alpha-Synuclein
  • Levodopa