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ACS Chem Neurosci. 2019 Aug 21;10(8):3464-3478. doi: 10.1021/acschemneuro.9b00088. Epub 2019 Aug 2.

Differential Interactome and Innate Immune Response Activation of Two Structurally Distinct Misfolded Protein Oligomers.

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Centre for Misfolding Diseases, Department of Chemistry , University of Cambridge , CB2 1EW Cambridge , U.K.
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER) - Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC) , Universidad Pablo de Olavide , 41092 Seville , Spain.
Department of Medical Biochemistry, Molecular Biology and Immunology , University of Seville , 41092 Seville , Spain.
Cambridge Centre for Proteomics, Systems Biology Centre, Department of Biochemistry , University of Cambridge , CB2 1GA Cambridge , U.K.
Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry , University of Florence , 50134 Florence , Italy.


The formation of misfolded protein oligomers during early stages of amyloid aggregation and the activation of neuroinflammatory responses are two key events associated with neurodegenerative diseases. Although it has been established that misfolded oligomers are involved in the neuroinflammatory process, the links between their structural features and their functional effects on the immune response remain unknown. To explore such links, we took advantage of two structurally distinct soluble oligomers (type A and B) of protein HypF-N and compared the elicited microglial inflammatory responses. By using confocal microscopy, protein pull-down, and high-throughput mass spectrometry, we found that, even though both types bound to a common pool of microglial proteins, type B oligomers-with a lower solvent-exposed hydrophobicity-showed enhanced protein binding, correlating with the observed inflammatory response. Furthermore, the interactome associated with inflammatory-mediated neurodegeneration revealed previously unidentified receptors and signaling molecules likely to be involved in the oligomer-elicited innate immune response.


Misfolded oligomers; innate immunity; molecular mechanisms; neurodegenerative disease; neuroinflammation; protein misfolding

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