Size-Selective Phagocytic Clearance of Fibrillar α-Synuclein through Conformational Activation of Complement Receptor 4.
Kristian Juul-MadsenPer QvistKirstine L BendtsenAnnette Eva LangkildeBente VestergaardKenneth A HowardMartxel Dehesa-EtxebesteSoren Riis PaludanGregers Rom AndersenPoul Henning JensenDaniel E OtzenMarina Romero-RamosThomas Vorup-JensenPublished in: Journal of immunology (Baltimore, Md. : 1950) (2020)
Aggregation of α-synuclein (αSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded αSN from human and rodent neurons is relevant to the progression and spread of αSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular αSN. This study found that human complement receptor (CR) 4 selectively bound fibrillar αSN, but not monomeric species. αSN is an abundant protein in the CNS, which potentially could overwhelm clearance of cytotoxic αSN species. The selectivity of CR4 toward binding fibrillar αSN consequently adds an important αSN receptor function for maintenance of brain homeostasis. Based on the recently solved structures of αSN fibrils and the known ligand preference of CR4, we hypothesize that the parallel monomer stacking in fibrillar αSN 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 αSN 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 αSN 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.
Keyphrases
- parkinson disease
- endothelial cells
- immune response
- deep brain stimulation
- binding protein
- gene expression
- spinal cord
- machine learning
- single cell
- white matter
- chronic kidney disease
- high glucose
- ejection fraction
- blood brain barrier
- single molecule
- brain injury
- spinal cord injury
- genome wide
- oxidative stress
- patient reported outcomes
- transcription factor
- electronic health record
- rna seq
- multiple sclerosis
- simultaneous determination
- diabetic rats
- dna binding
- liquid chromatography