14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic α-synuclein

Bing Wang, Rachel Underwood, Anjali Kamath, Colleen Britain, Michael B. McFerrin, Pamela J. McLean, Laura A. Volpicelli-Daley, Robert H. Whitaker, William J. Placzek, Katelyn Becker, Jiyan Ma, Talene A. Yacoubian

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

α-Synuclein (αsyn) is the key protein that forms neuronal aggregates in the neurodegenerative disorders Parkinson’s disease (PD) and dementia with Lewy bodies. Recent evidence points to the prion-like spread of αsyn from one brain region to another. Propagation of αsyn is likely dependent on release, uptake, and misfolding. Under normal circumstances, this highly expressed brain protein functions normally without promoting pathology, yet the underlying endogenous mechanisms that prevent αsyn spread are not understood. 14-3-3 proteins are highly expressed brain proteins that have chaperone function and regulate protein trafficking. In this study, we investigated the potential role of the 14-3-3 proteins in the regulation of αsyn spread using two models of αsyn spread. In a paracrine αsyn model, 14-3-3θ promoted release of αsyn complexed with 14-3-3θ. Despite higher amounts of released αsyn, extracellular αsyn showed reduced oligomerization and seeding capability, reduced internalization, and reduced toxicity in primary mixed-gender mouse neurons. 14-3-3 inhibition reduced the amount of αsyn released, yet released αsyn was more toxic and demonstrated increased oligomerization, seeding capability, and internalization. In the preformed fibril model, 14-3-3 θ reduced αsyn aggregation and neuronal death, whereas 14-3-3 inhibition enhanced αsyn aggregation and neuronal death in primary mouse neurons. 14-3-3s blocked αsyn spread to distal chamber neurons not exposed directly to fibrils in multichamber, microfluidic devices. These findings point to 14-3-3s as a direct regulator of αsyn propagation, and suggest that dysfunction of 14-3-3 function may promote αsyn pathology in PD and related synucleinopathies.

Original languageEnglish (US)
Pages (from-to)8211-8232
Number of pages22
JournalJournal of Neuroscience
Volume38
Issue number38
DOIs
StatePublished - Sep 19 2018

Keywords

  • 14-3-3 proteins
  • Aggregation
  • Dementia with lewy bodies
  • Exosome
  • Parkinson’s disease
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wang, B., Underwood, R., Kamath, A., Britain, C., McFerrin, M. B., McLean, P. J., Volpicelli-Daley, L. A., Whitaker, R. H., Placzek, W. J., Becker, K., Ma, J., & Yacoubian, T. A. (2018). 14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic α-synuclein. Journal of Neuroscience, 38(38), 8211-8232. https://doi.org/10.1523/JNEUROSCI.1134-18.2018