| Autor: |
Konstantoulea, Katerina, Guerreiro, Patricia, Ramakers, Meine, Louros, Nikolaos, Aubrey, Liam D, Houben, Bert, Michiels, Emiel, De Vleeschouwer, Matthias, Lampi, Yulia, Ribeiro, Luís F, de Wit, Joris, Xue, Wei‐Feng, Schymkowitz, Joost, Rousseau, Frederic |
| Předmět: |
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| Zdroj: |
EMBO Journal; Jan2022, Vol. 41 Issue 2, p1-23, 23p |
| Abstrakt: |
It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self‐assembly of short protein segments called aggregation‐prone regions (APRs) that favour cross‐β structure. Here, we investigated whether Aβ amyloid assembly can be modified by heterotypic interactions between Aβ APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of Aβ plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the Aβ APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify Aβ assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an Aβ reporter cell line promote Aβ amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where Aβ self‐aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid‐deposition diseases. Synopsis: Amyloid diseases are driven by self‐assembly of cross‐beta‐structured amyloid fibrils via short aggregation prone regions (APRs). In the case of the Aβ model, local homology can lead to heterotypic interactions between the amyloid and the proteome, which in turn modulate the assembly kinetics and morphology of amyloid fibrils. Hundreds of human proteins show local homology to the aggregation prone regions of AβSome peptides corresponding to such homologous sequences modify Aβ aggregation in vitro and in cellsPlaques from AD patients are enriched with proteins that contain regions that are homologous to the APRs of AβOur results suggest that heterotypic amyloid interactions may contribute to the phenomenon of selective vulnerability of certain cell types of amyloid deposition [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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