Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

• Published in: EMBO molecular medicine Vol. 7; no. 3; pp. 339 - 356
• Main Authors: Lau, Agnes, McDonald, Alex, Daude, Nathalie, Mays, Charles E, Walter, Eric D, Aglietti, Robin, Mercer, Robert CC, Wohlgemuth, Serene, Merwe, Jacques, Yang, Jing, Gapeshina, Hristina, Kim, Chae, Grams, Jennifer, Shi, Beipei, Wille, Holger, Balachandran, Aru, Schmitt‐Ulms, Gerold, Safar, Jiri G, Millhauser, Glenn L, Westaway, David
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2015; EMBO Press; BlackWell Publishing Ltd; Springer Nature
• Subjects: Alzheimer's disease; Amino acids; Animals; Bovine spongiform encephalopathy; Brain research; Cell Line; copper; Creutzfeldt-Jakob disease; Disease Models, Animal; DNA Mutational Analysis; endoproteolysis; Histocytochemistry; Humans; Infectious diseases; Infectivity; Mice, Transgenic; Microscopy; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Myelination; Nervous system diseases; octarepeats; Pathogenesis; Peptides; Peripheral nerves; prion; Prion Diseases - pathology; Prion Diseases - physiopathology; Prion protein; Prions; Protein Conformation; Protein Processing, Post-Translational; Protein structure; Proteins; Proteolysis; PrPC Proteins - chemistry; PrPC Proteins - metabolism; Signal transduction; Studies; Transgenic mice; Canada; endoproteolysis; copper; octarepeats; prion; C2
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404588

The cellular prion protein (PrPC) comprises a natively unstructured N‐terminal domain, including a metal‐binding octarepeat region (OR) and a linker, followed by a C‐terminal domain that misfolds to form PrPSc in Creutzfeldt‐Jakob disease. PrPC β‐endoproteolysis to the C2 fragment allows PrPSc formation, while α‐endoproteolysis blocks production. To examine the OR, we used structure‐directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion‐infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal‐catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. Synopsis Flexibility in the N‐terminal octarepeat region of the prion protein affects endoproteolysis and disease pathology in transgenic mice. Beyond Creutzfeldt‐Jakob disease, the prion mechanism has implications for other misfolding diseases like Alzheimer's or Parkinson's disease. β‐cleavage of PrP was influenced by the octarepeat region using a mechanism independent from metal‐catalysed hydrolysis. Modulating the flexibility of the PrP octarepeat region uncoupled PrPSc levels from the onset of disease. The octarepeat region acts like a clutch to drive neurological disease. Flexibility in the N‐terminal octarepeat region of the prion protein affects endoproteolysis and disease pathology in transgenic mice. Beyond Creutzfeldt‐Jakob disease, the prion mechanism has implications for other misfolding diseases like Alzheimer's or Parkinson's disease.