Presentation by:

Stephie Abraham

What is CJD??What is CJD??

It is a rare, degenerative, and fatal It is a rare, degenerative, and fatal brain disorder.brain disorder.

Alternative name:Alternative name:– Transmissible Spongiform Transmissible Spongiform

EncephalopathyEncephalopathy Commonly affects people above 60.Commonly affects people above 60. 90% of patients die within a year.90% of patients die within a year.

3 Types3 Types

Sporadic CJDSporadic CJD– Most commonMost common– Appears in a person with no known risk Appears in a person with no known risk

factors.factors.– 1 case per million in the US1 case per million in the US– Mean age is 62Mean age is 62

Hereditary CJDHereditary CJD– Appears in people who has had a family Appears in people who has had a family

history of CJD.history of CJD.– About 5-10% in the USAbout 5-10% in the US

Acquired CJDAcquired CJD– Exposure to infectious brain tissueExposure to infectious brain tissue– Least commonLeast common– Less than 1%Less than 1%

SymptomsSymptoms

Early Stages:Early Stages:– Problems with muscular coordinationProblems with muscular coordination– Personality changesPersonality changes– Impaired memoryImpaired memory– Impaired visionImpaired vision– MyoclonusMyoclonus– blindnessblindness

Later Stages:Later Stages:– Loss of ability to speak and moveLoss of ability to speak and move– Enter a comaEnter a coma– DeathDeath

CausesCauses

First theory:First theory:– CJD was caused by a slow-acting virusCJD was caused by a slow-acting virus

Problems:Problems:– The disease causing agent did not have The disease causing agent did not have

any characteristics similar to virus or any characteristics similar to virus or bacteria.bacteria. No nucleic acidNo nucleic acid Long incubation period- up to 40 yearsLong incubation period- up to 40 years Indestructible Indestructible

Second theorySecond theory– Proposed by Stanley Proposed by Stanley

PrusinerPrusiner– Disease was caused by Disease was caused by

PrionsPrions– Conformational change Conformational change

from cellular PrP to from cellular PrP to scrapie PrPscrapie PrP

PrionsPrions

““Proteinaceous infectious particle that Proteinaceous infectious particle that lacks a nucleic acid”lacks a nucleic acid”

Naturally occurring proteins in Naturally occurring proteins in mammalsmammals– Made of 253 amino acidsMade of 253 amino acids– High concentrations in the brain tissueHigh concentrations in the brain tissue– Initially encoded in chromosome 20 as Initially encoded in chromosome 20 as

amino acid residuesamino acid residues– Soluble in detergentsSoluble in detergents– Susceptible to enzyme digestionSusceptible to enzyme digestion

Rich in alpha-helical structure

N-terminal contains an octapeptide region

Disulfide linkage

PrP forms in PrP forms in the nucleus the nucleus

Translation of Translation of the ORFthe ORF

Endoplasmic Reticulum

Golgi Apparatus

Nucleus

Vesicles

Plasma Membrane

Post-translational Post-translational modificationsmodifications

Removal of the N-terminal 23 residue Removal of the N-terminal 23 residue signal peptidesignal peptide

Glycosylation at Asparagines 181 &197Glycosylation at Asparagines 181 &197 Formation of the disulfide bond Formation of the disulfide bond

between cysteine residues 179 & 214between cysteine residues 179 & 214 Proteolytic cleavage of the C-terminal Proteolytic cleavage of the C-terminal

24 amino acids24 amino acids Addition of Glycosyl Addition of Glycosyl

Phosphatidylinositol (GPI) anchorPhosphatidylinositol (GPI) anchor

Functions:Functions:– Cell adhesionCell adhesion– Signaling Signaling

processesprocesses– Copper transport Copper transport

or metabolismor metabolism

Scrapie PrP

Characteristics

• 43% beta sheet

• 30% alpha-helix

• Resistant to proteolytic digestion

• Insoluble in detergents

Scrapie PrP forces normal cellular PrP Scrapie PrP forces normal cellular PrP to change its form.to change its form.

Aggregates are formed Aggregates are formed Cell death occursCell death occurs

TreatmentTreatment– No known cureNo known cure

Current ResearchCurrent Research– Focused on the mechanism of Focused on the mechanism of

transformation of normal PrP to scrapie transformation of normal PrP to scrapie PrP. PrP.

Questions???Questions???

The End The End !!!!!!