Size-Selective Phagocytic Clearance of Fibrillar a-Synuclein through Conformational Activation of Complement Receptor 4

Aggregation of alpha-synuclein (alpha SN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded alpha SN from human and rodent neurons is relevant to the progression and spread of alpha SN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular alpha SN. This study found that human complement receptor (CR) 4 selectively bound fibrillar alpha SN, but not monomeric species. alpha SN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic alpha SN species. The selectivity of CR4 toward binding fibrillar alpha N consequently adds an important alpha SN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of alpha SN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar alpha SN creates a known danger-associated molecular pattern of stretches of anionic side chains strongly bound by CR4. Conformational change in the receptor regulated tightly clearance of fibrillar alpha SN by human monocytes. The induced change coupled concomitantly with phagolysosome formation. Data mining of the brain transcriptome in Parkinson disease patients supported CR4 as an active alpha SN clearance mechanism in this disease. Our results associate an important part of the innate immune system, namely complement receptors, with the central molecular mechanisms of CNS protein aggregation in neurodegenerative disorders.