Details

Autor(en) / Beteiligte

• Luk, Kelvin C.
• Covell, Dustin J.
• Kehm, Victoria M.
• Zhang, Bin
• Song, Insung Y.
• Byrne, Matthew D.
• Pitkin, Rose M.
• Decker, Samantha C.
• Trojanowski, John Q.
• Lee, Virginia M.-Y.

Titel

Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity

Ist Teil von

• Cell reports (Cambridge), 2016-09, Vol.16 (12), p.3373-3387

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson’s disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds and endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility. [Display omitted] •Alpha-Synuclein (α-Syn) cross-seeding is less efficient than homologous seeding•Sequence homology between α-Syn monomers and fibril seeds predicts seeding in vitro•Chimeric α-Syn fibrils vary greatly in their ability to induce pathology in neurons•Pathogenicity of α-Syn fibrils can be templated to non-homologous α-Syn monomers Luk et al. show that cross-seeding between human (Hu) and mouse (Ms) α-synuclein (α-Syn) is less efficient than homologous seeding. Using a series of Hu-Ms chimeric proteins, they show that these fibrils likely adopt distinct and transferable configurations that determine the ability to induce Parkinson’s disease-like pathology in neurons and in vivo.