CSB351Y1 Lecture Notes - Lecture 19: Transmissible Spongiform Encephalopathy, Edman Degradation, Prnp
26 May 2018
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Lecture 19: Prions
Introduction
• Bovine spongiform encephalopathy (BSE), scrapie of sheep and Creutzfeldt-Jakob disease (CJD) of humans
• Mad Cow Disease
Fundamental Concepts
• Prions are proteins that can cause fatal brain disease
• Human prion diseases can be transmitted or inherited
• Infectious agent of prion disease contains protein but no detectable nucleic acid
• We all have prion genes
• Prion hypothesis – misfolded forms can catalyze refolding of properly folded protein into misfolded
• Prion diseases of humans may have much in common with AD and PD
How is prion disease transmitted?
• Prion diseases or transmissible spongiform encephalopathies by inoculation or by dietary exposure to infected
tissues
• Transmission between different species unlikely – Species Barrier
• Scrapie in sheep → mink through meat → Transmissible Mink Encephalopathy (TME)
- Prion protein structures look very similar between animals however
• Beef originating from Scrapie sheep fed to cattle in recent epidemic
• Prio deried fro proteiaeous and infectious - lacks nucleic acid
PrP Research
• PrPSc = scrapie infectious and PrPc = cellular non-infectious
- Protease-resistant core of PrPSc and has molecular mass of 27-30 kDa
• Edman degradation → N-terminal sequence → predict nucleotide sequence → molecular cloning experiment
• mRNA levels identical infected vs. uninfected animals – PrPc (protease sensitive)
• cDNA probes for PrP → PrP expressed in uninfected adult brain
Pathology
• PrPSc is resistant to breakdown and removal from the body (proteases)
- Accumulates in the brain of patient with prion disease
• Amyloid plaques – prion protein clumps resistant to breakdown and removal
• Plaques of misfolded proteins also found in other diseases (AD, aging normal brain but proteins other than PrP)
Histology of prion diseases
• Prion disease affects central nervous system
• Prions cause:
- Kuru disease (trembling, walking and coordination difficulty, dementia)
- Creutzfeldt-Jakob (rare human dementia)
- Gerstmann-Straussler syndrome
- Scrapie in sheep (scraping of wool and etching)
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Document Summary
Introduction: bovine spongiform encephalopathy (bse), scrapie of sheep and creutzfeldt-jakob disease (cjd) of humans, mad cow disease. Prion protein structures look very similar between animals however: beef originating from scrapie sheep fed to cattle in recent epidemic (cid:862)prio(cid:374)(cid:863) deri(cid:448)ed fro(cid:373) protei(cid:374)a(cid:272)eous and infectious - lacks nucleic acid. Prp research: prpsc = scrapie infectious and prpc = cellular non-infectious. Pathology: prpsc is resistant to breakdown and removal from the body (proteases) Histology of prion diseases: prion disease affects central nervous system, prions cause: Kuru disease (trembling, walking and coordination difficulty, dementia) Prion protein structure: signal peptide, octameric repeats, hydrophobic core, sugar chain attachment (n-glycosylation) and gpi anchor, prp 33-35 undergoes serveral post-translational events to become prp 27-30: Iatrogenic cjd transmission of infections during medical procedures. Cjd and genetics: sporadic cjd influenced by genetics. T(cid:449)o (cid:374)or(cid:373)al alleles of prnp ge(cid:374)e (cid:894)(cid:1005)(cid:1006)9m a(cid:374)d (cid:1005)(cid:1006)9v(cid:895) i(cid:374)flue(cid:374)(cid:272)es a perso(cid:374)"s risk of disease a(cid:374)d for(cid:373) of disease.
