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CLINICAL ASPECTS OF BIOCHEMISTRY
NEURODEGENERATIVE DISEASES
Prion diseases
Alzheimer's disease
SOME PRION DISEASES
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Species
Transmission
Scrapie
Sheep
Infection
Bovine spongiform
encephalopathy (BSE)
Cow
Infection (contaminated feed)
Kuru
Human
Infection (cannibalism)
Creutzfeldt-Jakob disease
Iatrogenic
Familial
Sporadic
Human
Infection (growth hormone etc.)
Germline mutations of PrP gene
Somatic mutations of PrP gene or
spontaneous conversion
Infection (eating beef?)
New variant
Gertmann-StrausslerScheinker disease (GSS)
human
Germline mutations of PrP gene
Fatal familial insomnia (FFI) Human
Germline mutations of PrP gene
SPONGIFORM BRAIN TISSUE
From Prusiner (1998)
HOW CAN PROTEINACEOUS PARTICLE BE INFECTIOUS?
(a) May contain "shielded" nucleic acid?
(b) Proteins specify own aa sequence?
(c) Normal cells carry a gene that encodes PrP,
and the product is changed to a different
conformation by the infectious particle?
THE PRION HYPOTHESIS
TSEs occur when the normal ‘cellular’ form of the
prion protein (PrPc) is converted to the abnormal form
(PrPsc). PrPc and PrPsc differ in conformation. The
conversion is ‘autocatalytic’ - PrPsc facilitates the
conversion of more PrPc to PrPsc.
TSEs - MAIN TOPICS
1.
2.
3.
4.
5.
6.
7.
8.
9.
The nature of PrPc and PrPsc
Conversion of PrPc to PrPsc
Inherited TSEs
Species specificity and species barriers
Strains
Normal function; role in disease
Doppel
BSE and nvCJD
Therapies?
Normal (PrPc) and abnormal (PrPs) forms of prion protein
PrPc
•Precursor ~ 250 amino acids. Mature PrPc ~ 210 aas
•Hydrophobic glycoprotein
•GPI anchor (glucosyl phosphatidyl inositol)
•NMR structure - C-terminal end a-helical, N-terminal end
unordered
PrPsc
•Same sequence and postranslational modifications as PrPc
•Different conformation - more b-sheet
•Tends to form insoluble aggregates
•More resistant to proteolysis than PrPc
•Insoluble PrPsc (in amyloid plaques) not infectious?
PrPSc IS RESISTANT TO PROTEOLYSIS
-PK
+PK
PrPSc PrPC PrPSc PrPC
Based on Priola (2001)
STRUCTURE OF THE HUMAN PRION PROTEIN
Globular domain
Based on Rivera-Milla et al (2003)
HYPOTHETICAL MODELS FOR PrPc AND PrPsc
Based on Prusiner (1998)
alpha helix
beta sheet
PrPSc CAN CONVERT PrPC TO PrPSc IN VITRO
Based on Priola (2001)
TWO MODELS FOR CONVERSION OF PrPC TO PrPSc
PrPSc
PrPC
(a)
(b)
~6
Etc Etc
Very slow
fast
fast
fast
INHERITED FORMS OF CJD, GSS, FFI etc
Mutations may stabilise PrPsc conformation
e.g. P102L in GSS
[when this was engineered into mice they
developed 'scrapie')
Met/Val129 polymorphism in man - Val
homozygotes more susceptible to CJD? Met
homozygotes more susceptible to nvCJD?
SOME POINT MUTATIONS IN THE PrP GENE THAT
CAUSE HUMAN PRION DISEASE
Position
Normal
Mutant
102
Pro
Leu
105
Pro
Leu
145
Ala
Stop
178
Asp
Asn
180
Val
Ile
200
Glu
Lys
Based on Priola (2001)
SPECIES BARRIERS TO TRANSFER OF PrPSc
Sequence differences between PrP from different species
may provide (and explain?) some barrier to infection - but
incomplete.
E.g. Mouse  mouse transfer gives more rapid infection
than mouse  hamster etc. But, mouse  hamster 
hamster gives faster infection, Homologous PrPSc is
better at converting PrPC than heterologous
STRAINS OF PRION DISEASES
Scrapie occurs as about 20 different strains
(differentiated by time taken to infect mice and
different behavioural effects). CJD occurs as 2-4
different strains. BSE only one.
May be explicable in terms of different conformations,
but the more strains the more far-fetched this
explanation. The biggest problem with the Prusiner
model?
For 2 CJD strains - evidence for different
conformations (pattern of proteolysis)
DIFFERENT PrPSc STRAINS - DIFFERENT CONFORMATIONS
-PK
+PK
Based on Priola (2001)
NORMAL FUNCTION OF PRPC
Not clear; knockout mice lacking PrP are not
seriously abnormal
Possible roles in cell signalling and in processing
copper ions have been suggested
WHY DOES PrPSc CAUSE DISEASE?
Possible explanations include:
• Neurotoxic
• Deposits disrupt cells
• Deposits disrupt intercellular contacts (synapses etc)
• Loss of PrPC
DOPPEL (Dpl)
A PrP-like protein (~25% sequence identity but shorter).
Gene close to PrP gene - could explain variable effect of PrP
knockouts
Involvement in prion diseases?
Based on Behrens & Aguzzi (2002)
ANNUAL INCIDENCE OF BSE IN THE UK
Number of BSE cases
40,000
30,000
20,000
10,000
16
83 663
85
86 87 88
89
90 91
92 93 94
Year of epidemic
95 96
nvCJD incidence
30
25
20
15
10
5
0
1994 1995 1996 1997 1998 1999 2000
2001 2002 2003 2004
Number of BSE cases
40,000
30,000
20,000
10,000
85 86 87 88 89 90 91 92 93 94 95 96
Year of epidemic
nvCJD incidence
30
25
20
15
10
5
0
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
CJD - POSSIBLE THERAPIES
• Drugs that stabilise PrPC (stabilise helical conformation)
• Drugs that inhibit aggregation & amyloid (b sheet) formation
• Immunization against PrPC or PrPSc