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The Effect of Fragmented Pathogenic ?-Synuclein Seeds on Prion-like Propagation.

ABSTRACT: Aggregates of abnormal proteins are widely observed in neuronal and glial cells of patients with various neurodegenerative diseases, and it has been proposed that prion-like behavior of these proteins can account for not only the onset but also the progression of these diseases. However, it is not yet clear which abnormal protein structures function most efficiently as seeds for prion-like propagation. In this study, we aimed to identify the most pathogenic species of ?-synuclein (?-syn), the main component of the Lewy bodies and Lewy neurites that are observed in ?-synucleinopathies. We prepared various forms of ?-syn protein and examined their seeding properties in vitro in cells and in mouse experimental models. We also characterized these ?-syn species by means of electron microscopy and thioflavin fluorescence assays and found that fragmented ? sheet-rich fibrous structures of ?-syn with a length of 50 nm or less are the most efficient promoters of accumulation of phosphorylated ?-syn, which is the hallmark of ?-synucleinopathies. These results indicate that fragmented amyloid-like aggregates of short ?-syn fibrils are the key pathogenic seeds that trigger prion-like conversion.

SUBMITTER: Tarutani A

PROVIDER: S-EPMC5009244 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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The Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation.

Tarutani Airi A Suzuki Genjiro G Shimozawa Aki A Nonaka Takashi T Akiyama Haruhiko H Hisanaga Shin-Ichi S Hasegawa Masato M

The Journal of biological chemistry 20160705 36

Aggregates of abnormal proteins are widely observed in neuronal and glial cells of patients with various neurodegenerative diseases, and it has been proposed that prion-like behavior of these proteins can account for not only the onset but also the progression of these diseases. However, it is not yet clear which abnormal protein structures function most efficiently as seeds for prion-like propagation. In this study, we aimed to identify the most pathogenic species of α-synuclein (α-syn), the ma ...[more]

PMID: 27382062

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Project description: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.SIGNIFICANCE STATEMENT Transfer of misfolded aggregates of α-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 α-synuclein. 14-3-3 proteins are highly expressed chaperone proteins that interact with α-synuclein and regulate protein trafficking. We used two different models in which toxicity is associated with cell-to-cell transfer of α-synuclein to test whether 14-3-3s impact α-synuclein toxicity. We demonstrate that 14-3-3θ reduces α-synuclein transfer and toxicity by inhibiting oligomerization, seeding capability, and internalization of α-synuclein, whereas 14-3-3 inhibition accelerates the transfer and toxicity of α-synuclein in these models. Dysfunction of 14-3-3 function may be a critical mechanism by which α-synuclein propagation occurs in disease.

Dataset Information

The Effect of Fragmented Pathogenic ?-Synuclein Seeds on Prion-like Propagation.

Publications

The Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation.

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