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Autoimmune responses to soluble aggregates of amyloidogenic proteins involved in neurodegenerative diseases: Overlapping aggregation prone and autoimmunogenic regions

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Abstract

Why do patients suffering from neurodegenerative diseases generate autoantibodies that selectively bind soluble aggregates of amyloidogenic proteins? Presently, molecular basis of interactions between the soluble aggregates and human immune system is unknown. By analyzing sequences of experimentally validated T-cell autoimmune epitopes, aggregating peptides, amyloidogenic proteins and randomly generated peptides, here we report overlapping regions that likely drive aggregation as well as generate autoantibodies against the aggregates. Sequence features, that make short peptides susceptible to aggregation, increase their incidence in human T-cell autoimmune epitopes by 4-6 times. Many epitopes are predicted to be significantly aggregation prone (aggregation propensities ≥10%) and the ones containing experimentally validated aggregating regions are enriched in hydrophobicity by 10-20%. Aggregate morphologies also influence Human Leukocyte Antigen (HLA)-types recognized by the aggregating regions containing epitopes. Most (88%) epitopes that contain amyloid fibril forming regions bind HLA-DR, while majority (63%) of those containing amorphous β-Aggregating regions bind HLA-DQ. More than two-Thirds (70%) of human amyloidogenic proteins contain overlapping regions that are simultaneously aggregation prone and auto-immunogenic. Such regions help clear soluble aggregates by generating selective autoantibodies against them. This can be harnessed for early diagnosis of proteinopathies and for drug/vaccine design against them.

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APA

Kumar, S., Mary Thangakani, A., Nagarajan, R., Singh, S. K., Velmurugan, D., & Michael Gromiha, M. (2016). Autoimmune responses to soluble aggregates of amyloidogenic proteins involved in neurodegenerative diseases: Overlapping aggregation prone and autoimmunogenic regions. Scientific Reports, 6. https://doi.org/10.1038/srep22258

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