Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

Abstract

A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…The PrPc monomer is a~209 amino acid (~200 kDa) glycosylated cell surface polypeptide, containing a predominant internal α-helical region, encoded in humans at chr 20p13. Normally, the constitutively expressed PrPc appears to be involved in neuritogenesis, neuronal homeostasis, cell signaling, cell-cell adhesion and interaction and intercellular communication; moreover, it may provide a protective role against multiple forms of induced physiological stress [56,60,75,84,86,88,89]. The misfolded, abnormal and insoluble isoform of PrPc known as PrPsc self-associates into pro-inflammatory, protease-resistant aggregates that are insoluble in most detergents and chaotropic agents [59,75,84,[89][90][91].…”

“…Normally, the constitutively expressed PrPc appears to be involved in neuritogenesis, neuronal homeostasis, cell signaling, cell-cell adhesion and interaction and intercellular communication; moreover, it may provide a protective role against multiple forms of induced physiological stress [56,60,75,84,86,88,89]. The misfolded, abnormal and insoluble isoform of PrPc known as PrPsc self-associates into pro-inflammatory, protease-resistant aggregates that are insoluble in most detergents and chaotropic agents [59,75,84,[89][90][91]. The molecular mechanisms of PrPsc neurotoxicity that drive the initiation, development and progression of PrD are highly complex and, similar to the case of AD, increased oxidative stress and chronic inflammation appear to be critically involved in the initiation and progression of PrD [5,73,86,[92][93][94][95].…”

microRNA-146a as a biomarker for transmissible spongiform encephalopathy

“…PrDs are known to be caused by a misfolded isoform of a highly conserved, ubiquitous brain-, central nervous system (CNS)-, peripheral nervous system (PNS)-and lymphoid tissue-enriched cellular prion sialoglycoprotein known as PrPc (prion protein -cellular). PrPc monomer is a 209 amino acid (MW ~200 kDa), predominantly α-helical glycosylated cell surface polypeptide, and the constitutively expressed PrPc appears to be involved in cell-cell adhesion, cell-cell interaction, intercellular signaling and communication, neuritogenesis and neuronal homeostasis, and may provide a protective role against induced physiological stress [4,7,9,10,19,26,46]. The misfolded, abnormal isoform of PrPc known as PrPsc self-associates into a pro-inflammatory, protease-resistant aggregate highly insoluble in most detergents [7,10,16,17,46].…”

“…PrPc monomer is a 209 amino acid (MW ~200 kDa), predominantly α-helical glycosylated cell surface polypeptide, and the constitutively expressed PrPc appears to be involved in cell-cell adhesion, cell-cell interaction, intercellular signaling and communication, neuritogenesis and neuronal homeostasis, and may provide a protective role against induced physiological stress [4,7,9,10,19,26,46]. The misfolded, abnormal isoform of PrPc known as PrPsc self-associates into a pro-inflammatory, protease-resistant aggregate highly insoluble in most detergents [7,10,16,17,46]. The mechanisms of PrPsc neurotoxicity that drive the initiation, development and progression of PrD are highly complex and like Alzheimer's disease (AD), increased oxidative stress and chronic inflammation appear to be critically involved in the initiation and progression of PrD [19,21].…”

Dimerization of the prion protein studied by site specific mutagenesis to p-benzoyl-L-phenylalanine

“…The protein's primary structure is highly conserved among mammals. The major regions and elments of the sequence (Figure 2a) [15], are as follows. Proceeding the signal sequence there is a short positively charged N-terminal patch, which plays role in various functions of PrP.…”