C-Reactive Protein: The Nexus Between Inflammation and Protein Misfolding Diseases

Abhishek Roy^1,2Johannes Zeller^1,3Tracy L Nero^2,4,5Johanna Klepetko⁶Steffen Ulrich Eisenhardt³Michael Parker^2,4,7James David McFadyen^1,2,8,9Karlheinz Peter^1,10,2,9*

• ¹Baker Heart and Diabetes Institute, Melbourne, Australia
• ²Department of Cardiometabolic Health, The University of Melbourne, Parkville, Victoria, Australia
• ³Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
• ⁴ACRF Rational Drug Discovery Centre, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
• ⁵Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
• ⁶Clinical Laboratory for Bionic Extremity Reconstruction, Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
• ⁷Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute The University of Melbourne Parkville, Melbourne, VIC., Australia
• ⁸Department of Clinical Haematology, The Alfred Hospital, Melbourne, Victoria, Australia
• ⁹The School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
• ¹⁰Department of Cardiology, The Alfred Hospital, Melbourne, Victoria, Australia

C-reactive protein (CRP), an acute-phase protein primarily produced by hepatocytes in response to pro-inflammatory cytokines, is a widely used clinical marker for inflammation and tissue damage. In its native state, CRP exists in a stable pentameric form called pCRP. Upon interaction with activated cell membranes, pCRP undergoes a transitional conformation change into activated pCRP (pCRP*) and subsequently fully dissociates into its monomeric subunits (mCRP). pCRP* and mCRP interact with C1q and thereby activate the classical complement system pathway and both exert pro-inflammatory effects on platelets and endothelial cells.Although classically recognized as a marker of acute inflammation, CRP is increasingly implicated in the pathogenesis of protein-misfolding pathologies, notably neurodegenerative diseases and amyloidosis. This review explores the complex interplay between CRP, encompassing its isoforms pCRP, pCRP*, and mCRP, and misfolded proteins, examining the specific contributions to inflammation and neurodegenerative disease pathogenesis. We analyze the clinical significance of variations in CRP levels in patients with protein-misfolding diseases, discuss underlying mechanisms, and highlight potential implications of these findings for drug discovery and therapeutic targeting of CRP.