Too much of a bad thing, kills you · Exon 9 Exon 8 Cytosol Lumen. PS1. I T V L A L I W N F V V M I...
Transcript of Too much of a bad thing, kills you · Exon 9 Exon 8 Cytosol Lumen. PS1. I T V L A L I W N F V V M I...
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Neurodegenerative Disease:Neurodegenerative Disease:Too much of a bad thing, kills youToo much of a bad thing, kills you
John Hardy Ph.D. NIA
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Pathology of Diseases
• Alzheimer’s disease: plaques (Aβ), tangles (tau) and often, Lewy bodies (α-synuclein).
• Prion disease: often PrP plaques; sometimes tangles; sometimes Lewy bodies.
• FTDP-17/Pick’s disease: tangles or Pick bodies (3-repeat tau).
• Progressive Supranuclear Palsy and Corticobasal Degeneration (tangles).
• Parkinson’s disease/Lewy body dementia: Lewy bodies.
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A Prescient Suggestion
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Alzheimer’s Disease
• Primary Deposited Protein is Aβ• Genes for Mendelian Forms are
– APP: precursor of Aβ– Presenilin 1 and 2: enzymes catalysing
production of Aβ from APP• Tangle (tau) and Lewy Bodies (α-
synuclein) are Secondary Pathologies.
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Exon 9Exon 8
Cytosol
Lumen
PS1
I T VL A
L IW N FV V
M I S
Y
VD
A
Y
VN
K G
HW
G
IG
Exon 5Exon 4
Exon 3Exon 4
HK
AG
YK
IK
SV
S
D
R
YT
K
GQ
YL113 I
114
F
T
PFL
VT L
MV
V A T
VC
V
V
V
I M
PS1-NTF
LT
L E E D EEDEEVVQ
Q
Q
NS
R
G
RP
NS GLP PEHGLSR
RS L N
SE
HD
M
TV NRSQ29
DNRE N30
AN
Q
S QY FLP PT AE LM1
RD
EQ
NH
Exon 7Exon 8
R
P
M
L
CP
TWL I
VS
Y
AI
VVL
258
AL
AL V
D257
KG
L P EW
T
R
EL
V AQ
EN
E
AL S
290LT
F
P
V
WL
M VN
E
MT291I
YS
A
GDP
EA
QRVR
SKNY SKExon 9Exon10 E
NA
V
R
Q
ES
DT
EA
ND
DG
GS E
FWE
ES319
T320
Exon11Exon12
N
IV AI
LI G
LC
T L LLI
F411
AL
A C410
L
DW
G
TT
F
KK
A
AL
I
P
LP
SI
TF
F
GL
V
YF
AT
D
PS1-CTF
YL
VQ
PF
MD
A
QL
F
FQ
Y
H
I467
Exon11Exon10V
LKL GF I F
VYV
R377
D
G
G
L
G378
S
K
SAA
AS
T
R
S
T
E E
LEQV
AA
SE
P
E A Q R D HSL G P
DP
E
LAG
ISS
RS
H
Exon 6Exon 5
Exon 7Exon 6
V
KT
F
LG183
E184
AII
SL
LF FF I Y
H
L
FS
SL
W
L
YK160
IV161
V
LIS
HL
QR
A
G
T
TD
TFE
P
E
A
L
A
SV
VI
I
VI
L VV
NM
IM T
L
RC
KY
YR
P
LY AL
QIM I S
LA
VI
L
KY
Q
F
AL M
Exon 16Exon 17
KSN
K
Q
D
GV
Y
FF A E
HH V
F
G S DR
V
HE
A EK
K
M
APP
LM
IT
TA I V VG G VLMG I
V
I A G
V
L
VI
β secretase
α secretase
APP-NTF ...
...APP-CTF
ESIEETK D
VL
γ secretase
VM
293
Presenilinase
292
D257
D385
Exon 9Exon 8
APP-CTF
γ secretase
Presenilinase
CP
W
SY
IL
A VD
R
QE
NE
AL S
LT
F
P
V
WL
M VN
E
MTIYS
A
GDP
EA
VLF
YD
L
G
S
E E
DP
E
LAG
ISS
K
L MIT
TA I V VG G VLMG I
V
I A G
V
L
VI
...
293
292
257
385
GV
Q
April 1999
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Membrane
APP wild-type
αβ
Membrane
APP 670/1 Mutation
αβ
3 kD fragment(p3)
Mainly Aβ40
Released intoextracellular fluid
αSecretases
γ
β
γ
Less3 kD fragment
(p3)
Released intoextracellular fluid
Moretotal Aβ
Deposited
β
γ
+αSecretases
γ
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Membrane
APP 717 Mutations
αβ
Membrane
APP 692 Mutation
αβ
Released intoextracellular fluid
More Aβ42
Deposited
3 kD fragment(p3)
β
γ
PRESENILIN MUTATIONS HAVE SAME
EFFECT
α
γ
Released intoextracellular fluid
Moretotal Aβ
Deposited
3 kD fragment(p3)
βαSecretases
γ γ
-
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APP Probably a Locus for “Sporadic” Alzheimer’s Disease
July 1999
Oct. 2001
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Conclusion on Alzheimer’s Disease
• Overexpression of APP in Down syndrome causes disease.
• Overproduction of Aβ42 because of APP or presenilin mutations causes disease in a mendelian fashion.
• Genetic variability in ‘normal’ APP expression contributes to disease risk.– (not clear whether variability in presenilin expression
also contributes).
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Prion Diseases
• Primary protein deposit is PrPSc: sometimes as plaques, more often much more subtle.
• Hereditary (caused by prion gene mutations).• Sporadic (of unknown cause)• Infectious (iatrogenic, cannibalistic or infectious)• Tangle (tau) and Lewy Bodies (α-synuclein) can
be Secondary Pathologies.
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The First Family with a Prion Mutation
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Prion Disease Conclusions• Mutations in prion gene cause mendelian disease.• Homozygosity at codon 129 prediposes to infectious disease: whether
it is MM or VV depends on the sequence of the infecting prion.• Homozygosity of either allele predisposes to sporadic CJD.• Particular promoters, presumably high expressing ones, also
predispose to sporadic CJD.• But the promoter association does not hold up for infectious disease.• Thus, the mechanism of initiation of infectious disease is different
from that of sporadic disease (the former is not concentration dependent but the latter is?)
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Disease with only Tau Pathology
• FTDP-17 (previously, many families would have been called Pick’s disease): mendelian disease with variable pathology: tangles, Pick bodies or wispy tau filaments.
• Progressive Supranuclear Palsy, Corticobasal degeneration, Argyrophilic Grain Disease
• Parkinson’s Dementia Complex of Guam• Many other rare diseases including von
Economo’s disease and subacute sclerosing panencephalitis.
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The microtubule associated protein tau
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
Tau 3 repeat protein isoforms
Tau 4 repeat protein isoforms
352
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
3812+
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
4102+ 3+
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
38310+
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
4122+ 10+
1 2 3-1 4 4A 5 6 7 8 9 10 11 12 13 14
Tau gene
4412+ 3+ 10+
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June 1998
June 1998
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Tau Exon 10 3’ splice site mutations increase U1 snRNP binding and splicing of Exon 10
G-U-C-C-A-U-U-C-A-U-A
U1 snRNP
Splicesite
Exon 10
U
ACU
C
GA U
G
GUG
C
CAA
ACC
GU
AC
U
U (+16)
G (+13)U (+14)
(+3) A
(-2) A
U (+12)x
x
xxx
x
U1 snRNP
G-U-C-C-A-U-U-C-A-U-A
-C-A-G-U-G-U-G-A-G-U-A-C-C-U-U-C-A-C-A-C-G-U-Exon 10A A U G UU
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Evolution of Human tau haplotypes (no recombination between H1/H2)
H1 H29iiiG
(+)Multiple independent mutagenic events (9iii)
1 2 3 9i 9ii 11 13 1 2 3 9i 9iia3
13A11
C9iiiG
(-)
A C A A T a0 G T G T G G C
Slippage of a0 to a1/a2
H1 (9iii)
a09iiiA
1 2 3 9i 9ii 11 13 Slippage of a3 to a4A C A A T G T
(+) H2 (a4)
a1/a2 G119ii
iG
(+)
H1 (a1/a0)1 2 3 9i 9ii 13 1 2 3 9i 9ii
a49iiiG
(-)
11 13A C A A T T G T G G C A C
(+)/(-) indicates location of intronic deletion 5’ of E10
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April 1999
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Worldwide Distribution of Tau Haplotype
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Results
• LD extends almost the same distance in all populations (1.6Mb)
• Some breakdown at the teleomeric edge
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Inversion
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Haplotype dating
• Inversion/LD block implies distinct evolutions for each haplotype because there is suppressed recombination between the two haplotype clades
• Performed 2 analyses to determine the evolutionary distance between H1 and H2
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Comparison of chimp and human sequence
• neither haplotype is the founder of the other, since chimp at some level resembles either haplotype
• H1/H2 diverged from ~3 million years ago (also DeCode and Antwerp data)
GAGrs752141461242
CTCrs946841457408
TCCrs73396641445400
-++ins/del941442488GAGsthQ7R41432502
GAGrs105255341429726ATTrs75451241411483
GAGrs221739441409284GCCrs76705841354620
GTCrs388579641336326AGGrs156031041334330
TCCrs186432541333623AGArs205579441307507
CTCrs107883041301910H2H1ChimpdbSNP IDPosition
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Slippage of dinucleotide repeat markers
868 (21,700)62%24044475319Tau Hap 7243 (6,075)87%49644439826Tau Hap 6267 (6,675)86%25844423308Tau Hap 5542 (13,550)74%18345289761Tau Hap 3513 (12,825)75%18244752820Tau Hap 2
Predicted Age in Generations
(Years)
Major allele
frequency
Major Allele Size
LocationMarker name
• Assuming that H2 is a single founder event and an average of 25generations for each slippage event, typed 13 CEPH H2 homozygotes with microsatellite markers mapping to the region.
• The age of H2 in H. sapiens is ~10,000-30,000 years based on distribution and slippage.
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H2 has been re-introduced once exclusively into European H. sapiens populations
• Contradictory evolutionary evidence:– H1 and H2 diverged ~ 3M years ago– Yet, based on slippage analysis H2 is a recent
haplotype within H. sapiens (10-30K years ago)
• Further evidence:– H2 haplotype has reduced diversity compared with H1– H2 distribution reflects the spread of European
populations and is not seen within Asian and most African chromosomes
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H1, not H2 is Inverted!
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Model of the evolution of the MAPT locus
Ancestral -6M years
Chimp
H2 clade?
-3M yearsInversion
H1 clade
-0.03M yearsSingle form of H2 into H. sapiens
H. Sapiens H2 haplotype
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Tagging SNPs Selection
• 25 SNPs spanning the entire locus were selected from the CEPH database (www.hapmap.org)
• Using the program Tagit (popgen.biol.ucl.ac.uk/software) 5 SNPs were identified that captured the haplotype diversity of the MAPT locus
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More Complex than Just H1/H2
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Dissecting H1 further…
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Associations with PSP… and AD
(321)0.000006
(360)0.006
(272)(n) ‘p’
564855Others
24149H1c
141513H1b
62323H2a
PSPAlzheimer Disease
Controls
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MAPT and meta-analysishttp://www.alzforum.org/res/com/gen/alzgene/default.asp
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Primary Tauopathies• Mutations in the opening reading frame or in the exon 10
splice area cause mendelian tau disease (FTDP-17): the precise tau pathology is largely dependent on the mutation.
• Sporadic tangle diseases, PSP and CBD are predisposed to by the tau H1 haplotype.
• Weaker association of same haplotypes with Alzheimer’s disease.
• Other sporadic tangle diseases are either not assessed (too rare) or occur in populations without an H2 allele (Guam).
• Not clear whether haplotype association reflects differences in splicing or in expression (though overexpressing mice get tangles).
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Diseases with only Lewy Bodies
• Parkinson’s disease• Lewy body dementia
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June 1997
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Aug. 2001
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Iowa Kindred Structure
Laboratory of Neurogenetics, National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging
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Diffuse α-synuclein pathologies in male patient: abnormal neuronal and glial inclusions and processes
Globus pallidus
Substantia nigra
Hippocampus
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Chromosomal Spreads (FISH)
Laboratory of Neurogenetics, National Institute on Aging
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Lewy Bodies Disease Conclusions
• Mutations in α-synuclein can cause either mendelian Parkinson’s disease or Lewy Body dementia, sometimes both in the same family.
• Triplication (overall doubling) of the α-synuclein locus causes disease onset in the 30’s (duplication of the locus, causes disease in the 50’s)
• Genetic variability in the normal promoter contributes to risk of sporadic disease with high expression promoters being more prone to disease.
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Overall Conclusions• Analysis of autosomal dominant forms of neurodegenerative diseases
in which there is pathological deposition reveal that the causative locus encodes the protein which is deposited (most cases) or the enzymes responsible for the liberation of the deposited peptide (presenilins).
• Normal genetic variability at these same loci contribute to the risk of sporadic forms of these diseases: most likely, high expressors are predisposed to disease.
• Predictions and Implications– Deposition is clearly important.– SOD and sporadic ALS?– Genetic variability in degradation may also contribute to risk?
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Whole Genome Study For AD (presently underpowered ~180 cases and controls)
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Loss of Heterozygosity (10% North American Controls Show Evidence for
Consanguinity
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Sample Whole Genome DataChromosome 5 Control Male of 65 years