Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded brain proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases were found to exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics, genomics and immunopeptidomics databases. First, we retrieved at the mRNA and protein levels the expression patterns of common neurodegeneration-associated genes in two professional antigen-presenting cells, namely B-cells and dendritic cells. Surprisingly, we found that under physiological conditions, numerous neurodegeneration-associated proteins are abundantly expressed by human B-cells. Moreover, a survey of the human proteome allowed us to map a unique protein-protein interaction network linking common neurodegeneration-associated proteins and their first shell interactors in human B-cells. Network connectivity analysis identified two major hubs that both relate with inflammation and autophagy: the neurodegeneration-associated protein SQSTM1 (Sequestosome-1) and the signaling molecule TRAF6 (TNF Receptor Associated Factor 6). Interestingly, the mapped network also comprised two hub proteins involved in both inflammation and autoimmunity: HSPA8 (Heat Shock Protein Family A Member 8 also known as HSC70) and HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1). Finally, we explored the Immune Epitope Database (IEDB-AR) and found that a large share of neurodegeneration-associated proteins provide endogenous MHC class II-binding peptides in human B-cells. For several neurodegeneration-associated proteins such as amyloid beta A4 protein, sequestosome-1 and profilin-1, the reported MHC class II restrictions of derived peptides covered multiple MHC class II alleles. In contrast, a limited set of neurodegeneration-associated proteins appeared to provide B-cell endogenous peptides whose binding properties are restricted to specific MHC class II alleles. This is notably the case for microtubule-associated protein tau, presenilin 2 and serine/threonine-protein kinase TBK1 from which derived peptides were exclusively reported to bind HLA-DR15, a recently-identified susceptibility gene for late onset Alzheimer9s disease. Overall, our work indicates that immunization against neurodegeneration-associated proteins might be a physiological process which is shaped, at least in part, by B-cells.