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Mechanism of disaggregation of Tau fibrils in vivo

ABSTRACT: The interactome of fibrillar aggregates of the Tau repeat domain fused to YFP (TauRD-Y) was analyzed in HEK293T cells using SILAC. TauRD-Y was immunoprecipitated with anti-GFP antibody from lysates of SILAC-labeled cells expressing TauRD-Y in soluble form (light labeled; L), from cells containing aggregated TauRD-Y in nucleus and cytosol (medium labeled; M), and from cells containing aggregated TauRD-Y mainly localized to the cytoosl (heavy-labeled; H).

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Roman Körner

LAB HEAD: F. Ulrich Hartl

PROVIDER: PXD023400 | Pride | 2022-12-09

REPOSITORIES: Pride

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			Action	DRS
	20150703_Exactive_IS_14141.raw	Raw
	20150703_Exactive_IS_14142.raw	Raw
	20150703_Exactive_IS_14143.raw	Raw
	20150703_Exactive_IS_14144.raw	Raw
	20150703_Exactive_IS_14145.raw	Raw

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Project description:Amyloidlike fibrils are found in many fatal diseases, including Alzheimer's disease, type II diabetes mellitus, transmissible spongiform encephalopathies, and prion diseases. These diseases are linked to proteins that have partially unfolded, misfolded, and aggregated into amyloidlike fibrils. The kinetics of amyloidlike fibrils aggregation is still hotly debated and remains an important open question. We have utilized the GNNQQNY crystal structure and high-temperature molecular dynamics simulation in explicit solvent to study the disaggregation mechanism of the GNNQQNY fibrils and to infer its likely aggregation pathways. A hexamer model and a 12-mer model both with two parallel beta-sheets separated by a dry side-chain interface were adopted in our computational analysis. A cumulative time of 1 micros was simulated for the hexamer model at five different temperatures (298 K, 348 K, 398 K, 448 K, and 498 K), and a cumulative time of 2.1 micros was simulated for the 12-mer model at four temperatures (298 K, 398 K, 448 K, and 498 K). Our disaggregation landscape and kinetics analyses indicate that tetramers probably act as the transition state in both the hexamer and the 12-mer simulations. In addition, the 12-mer simulations show that the initial aggregation nucleus is with eight peptides. Furthermore, the landscape is rather flat from 8-mers to 12-mers, indicating the absence of major barriers once the initial aggregation nucleus forms. Thus, the likely aggregation pathway is from monomers to the initial nucleus of 8-mers with tetramers as the transition state. Transition state structure analysis shows that the two dominant transition state conformations are tetramers in the 3-1 and 2-2 arrangements. The predominant nucleus conformations are in peptide arrangements maximizing dry side-chain contacts. Landscape and kinetics analyses also indicate that the parallel beta-sheets form earlier than the dry side-chain contacts during aggregation. These results provide further insights in understanding the early fibrils aggregation.

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Mechanism of disaggregation of Tau fibrils in vivo

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