| First Author | Wang B | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 38 | Pages | 8211-8232 |
| PubMed ID | 30093536 | Mgi Jnum | J:266842 |
| Mgi Id | MGI:6200211 | Doi | 10.1523/JNEUROSCI.1134-18.2018 |
| Citation | Wang B, et al. (2018) 14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic alpha-Synuclein. J Neurosci 38(38):8211-8232 |
| abstractText | alpha-Synuclein (alphasyn) 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 alphasyn from one brain region to another. Propagation of alphasyn 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 alphasyn 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 alphasyn spread using two models of alphasyn spread. In a paracrine alphasyn model, 14-3-3theta promoted release of alphasyn complexed with 14-3-3theta. Despite higher amounts of released alphasyn, extracellular alphasyn 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 alphasyn released, yet released alphasyn was more toxic and demonstrated increased oligomerization, seeding capability, and internalization. In the preformed fibril model, 14-3-3 theta reduced alphasyn aggregation and neuronal death, whereas 14-3-3 inhibition enhanced alphasyn aggregation and neuronal death in primary mouse neurons. 14-3-3s blocked alphasyn 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 alphasyn propagation, and suggest that dysfunction of 14-3-3 function may promote alphasyn pathology in PD and related synucleinopathies.SIGNIFICANCE STATEMENT Transfer of misfolded aggregates of alpha-synuclein from one brain region to another is implicated in the pathogenesis of Parkinson's disease and other synucleinopathies. This process is dependent on active release, internalization, and misfolding of alpha-synuclein. 14-3-3 proteins are highly expressed chaperone proteins that interact with alpha-synuclein and regulate protein trafficking. We used two different models in which toxicity is associated with cell-to-cell transfer of alpha-synuclein to test whether 14-3-3s impact alpha-synuclein toxicity. We demonstrate that 14-3-3theta reduces alpha-synuclein transfer and toxicity by inhibiting oligomerization, seeding capability, and internalization of alpha-synuclein, whereas 14-3-3 inhibition accelerates the transfer and toxicity of alpha-synuclein in these models. Dysfunction of 14-3-3 function may be a critical mechanism by which alpha-synuclein propagation occurs in disease. |
