The document discusses the history and biology of prions. It covers: - Key historical prion disease discoveries from the 1730s to 2005. - The cellular trafficking and structures of normal PrPc and pathogenic PrPsc proteins. - How PrPsc is able to induce the misfolding of PrPc and replicate. - Characteristic features of prions like resistance to heat, enzymes, and their ability to spontaneously induce misfolding.

1. Franky Lamare
Msc 2nd Semester
Roll no. BCH-10

2. •1730’s found in English sheep
•1950-kuru
•1960’s-transmittance nature
•1980’s- CJD
•1982- Dr. Stanley Prusnier coins
the term prion.
•1990s- mad cow disease
•2005- new variant of CJD from
beef.
History of prion

3.  PrPc is expressed in neuronal cells as a membrane bound protein with two
glycosylation sites; it has the N-terminal domain (residues 23–127) is highly
flexible, and the C-terminal globular domain (residues 128–228) with the
internal hydrophobic amino acid residues which is structured in various
species. PrPc is normally imported into the endoplasmic reticulum (ER)
and targeted to the outer leaflet of the plasma membrane via a
glycosylphosphatidylinositol (GPI) anchor. However, several conditions,
such as ER stress or some pathogenic mutations in the PrP gene, can
induce the mislocalization of PrP in the cytosol, where it has a neurotoxic
potential as demonstrated in cell culture and transgenic mouse models
 PrPc : Normal cellular isoform
:Rich in alpha helix
The protein structure of prions in sheep involves 256 amino acids, 253 in
humans and 264 in bovine.
 Many different func-tions have been attributed to PrPc including
immunoregulation, signal transduction, cop-per binding, synaptic
transmission, induction of apoptosis or protection against apoptoti stimuli,
and many others

4. DNA
RNA Ribosome
Native protein Misfolded protein
Chaperones
Ubiquitin
ATP
Degraded protein
Loss of protein function (Cystic fibrosis)
Proteasome
Aggregate/fibrillar amyloid
Gain of toxicity
(Alzheimer disease)
Accumulation
(Amyloidoses)

6.  Mutation in the PRNP gene of the prion protein
 The “prion hypothesis “ explained by Stanley pruisser asserts
that a pathologic conformational variant of the prion protein,
denoted PrPsc induces endogenous natively folded prion
protein, PrPc t o misfold and itself become PrPsc by
modification o f secondary and tertiary structure in a process
of template directed misfolding for example tau in Alzheimer’s
and α- sinuclein in Parkinson’s disease and superoxide
dismutase1 in familial amyotrophic lateral sclerosis
 Mutation in the N termnal domain or within the hydrophobic
domain or increased synthesis of Prpc proteins
 others include ph and acidity ;increased salt content etc

7.  1 manlgcwmlv lfvatwsdlg lckkrpkpgg
wntggsrypg qgspggnryp pqggggwgqp
61 hgggwgqphg ggwgqphggg wgqphgggwg
qgggthsqwn kpskpktnmk hmagaaaagas
121 vvgglggyml gsamsrpiih fgsdyedryy
renmhrypnq vyyrpmdeys nqnnfvhdcv
181 nitikqhtvt tttkgenfte tdvkmmervv
eqmcitqyer esqayyqrgs smvlfssppv
241 illisflifl ivg

9. A PRION( PROteinaceous INfectious
particle.)is a self replicating protein which
are the main cause of a wide range of
neurodegenerative disorders
Lacks nucleic acid
PrPsc : Disease causing isoform
:Rich in beta pleated
PrPSc has the ability to convert PrPc to Itself
aided by “Proteinase-X”

10. Cellular trafficking of PrPC and PrPSc. PrPC (yellow dots) follows the secretory pathway of the cell through the endoplasmic
reticulum (ER) and the Golgi. Mature PrPC is inserted via its GPI anchor into plasma membrane lipid rafts. The conversion of PrPC
to PrPSc (orange ovals) occurs either on the cell surface or, following endocytosis, in a cellular compartment such as the endosome.
PrPSc formed at the surface and released into the extracellular space may cause the plaques seen in TSE diseases such as human
vCJD. The diffuse PrPSc deposits and neuronal vacuolation common to many sheep scrapie strains may be due to PrPSc formation
in endocytic compartments or to endocytosed surface PrPSc accumulating inside the cell. Misfolded PrPC (squiggle) accumulating in
the cytosol may also trigger PrPSc formation. (Inset) Structure of PrPC showing the GPI anchor, the glycan chains, the copper-
binding octapeptide repeats, and the regions where the  helices and loop structure of PrPC (red, blue) may be converted to the 
sheets of PrPSc. ERAD, endoplasmic reticulum associated degradation.
Cellular trafficking of PrPC and PrPSc

11.  Normal
Dominant
alpha helix
 Easily
soluble
 Monomeric
 Digested by
Proteases
 Gene PRNP
(short arm of
chromosome
20)
 Disease causing
 Beta pleated
 Insoluble
 Multimeric
 Resistant to
digestion
 Reproduce by
binding to PrPC
and stimulating
conversion of
PrPC into PrPsc

12.  Proteinaceous infectious particles
 Abnormal proteins that have an affinity for the
CNS
 Very highly resistant to heating (survive
routine autoclaving)
 Not sensitive to irradiation
 Not destroyed by enzymes that damage DNA or
RNA
 Sensitive to protein denaturing agents
Characteristic features of Prions

13. How are these abnormal proteins acquired?
 Spontaneous conversion
 A mutation in the prion gene in a brain
cell
 Inherit the abnormal gene from your
parents
 Ingestion of the protein
 Humans could be accidentally infected
with the protein (iatrogenic) Needles,
Tissue, Pituitary extracts

14.  1.IN HUMANS
 .Sporadic (85%)
• Creutzfeldt-Jakob disease (CJD)
 .Familial (genetic) (15%)
• Familial CJD
• Gerstman-Straussler-Scheinker Syndrome (GSS)
• Fatal Familial Insomnia (FFI)
 .Acquired by transmission(rare)
• Kuru
• Iatrogenic CJD (neurosurgical instruments, dura mater grafts)
• Variant CJD
• 2.IN SHEEPS –Scrapie disease
• 3.IN COWS - Bovine spongiform encelopathy(BSE)

15.  Postmortem
• Microscopic pathology
• Immunohistochemistry
• ELISA, Immunoblotting
• Bioassay
 Antemortem
• Same techniques as above applied to:
• Brain biopsy
• Tonsil, lymph node, third eyelid biopsy, or rectal

16. Prevention
1. Don’t feed cows to cows
2. Destroy cow population once BSE found
3. Implement sensitive diagnostic tests to identify cows with
BSE before they show symptoms
There is no good way to destroy PrPsc in living material
Cure
SO FAR NO CURE!!!!

18. “thank you”