clinical aspects of biochemistry neurodegenerative diseases prion diseases alzheimer's disease
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CLINICAL ASPECTS OF BIOCHEMISTRY NEURODEGENERATIVE DISEASES Prion diseases Alzheimer's disease. SOME PRION DISEASES TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES. SPONGIFORM BRAIN TISSUE. From Prusiner (1998). HOW CAN PROTEINACEOUS PARTICLE BE INFECTIOUS?. - PowerPoint PPT PresentationTRANSCRIPT
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
New variant
Human
Infection (growth hormone etc.)
Germline mutations of PrP gene
Somatic mutations of PrP gene or spontaneous conversion
Infection (eating beef?)
Gertmann-Straussler-Scheinker 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.
1. The nature of PrPc and PrPsc
2. Conversion of PrPc to PrPsc
3. Inherited TSEs4. Species specificity and species barriers5. Strains6. Normal function; role in disease7. Doppel8. BSE and nvCJD9. Therapies?
TSEs - MAIN TOPICS
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-helical, N-terminal end unordered
PrPsc
•Same sequence and postranslational modifications as PrPc
•Different conformation - more -sheet•Tends to form insoluble aggregates•More resistant to proteolysis than PrPc •Insoluble PrPsc (in amyloid plaques) not infectious?
PrPCPrPSc PrPCPrPSc
-PK +PK
PrPSc IS RESISTANT TO PROTEOLYSIS
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)
beta sheet
alpha helix
PrPSc CAN CONVERT PrPC TO PrPSc IN VITRO
Based on Priola (2001)
TWO MODELS FOR CONVERSION OF PrPC TO PrPSc
(a)
PrPC PrPSc
(b)
Etc Etc~6
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
Based on Priola (2001)
-PK +PK
WHY DOES PrPSc CAUSE DISEASE?
Possible explanations include:
• Neurotoxic
• Deposits disrupt cells
• Deposits disrupt intercellular contacts (synapses etc)
• Loss of PrPC
NORMAL FUNCTION OF PRPC
Not clear; knockout mice lacking PrP are not seriously abnormalPossible roles in cell signalling and in processing copper ions have been suggested
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
40,000
30,000
20,000
10,000
Num
ber
of B
SE
cas
es
85 86 87 88 89 90 91 92 93 94 95 96
16 83 663
Year of epidemic
nvCJD incidence
0
5
10
15
20
25
30
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
nvCJD incidence
0
5
10
15
20
25
30
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
40,000
30,000
20,000
10,000Num
ber
of B
SE
cas
es
85 86 87 88 89 90 91 92 93 94 95 96Year of epidemic
CJD - POSSIBLE THERAPIES
• Drugs that stabilise PrPC (stabilise helical conformation)
• Drugs that inhibit aggregation & amyloid ( sheet) formation
• Immunization against PrPC or PrPSc