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

Aggregation of alpha-synuclein (alphaSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded alphaSN from human and rodent neurons is relevant to the progression and spread of alphaSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular alphaSN. This study found that human complement receptor (CR) 4 selectively bound fibrillar alphaSN, but not monomeric species. alphaSN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic alphaSN species. The selectivity of CR4 toward binding fibrillar alphaSN consequently adds an important alphaSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of alphaSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar alphaSN 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 alphaSN 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 alphaSN 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.