Transcript Convergence Of Tau And Alpha

Clash Of The Titans! Convergence
Of Tau And Alpha-Synuclein
Amyloid In Neurodegenerative
Diseases
John Q. Trojanowski, M.D., Ph.D.
Institute on Aging
Center for Neurodegenerative Disease Research
Department of Pathology and Laboratory Medicine
University of Pennsylvania
Philadelphia, PA
Neurodegenerative Diseases
Characterized by Brain Amyloidosis
Disease
Lesions
Components
Parkinson’s Disease
LBs
-Synuclein
Dementia with Lewy Bodies
LBs
-Synuclein
Multiple System Atrophy
GCIs
-Synuclein
Alzheimer’s Disease
(Most common synucleinopathy!)
SPs
NFTs
LBs
Aβ
Tau
α-Synuclein
Prion diseases
SPs
Prions
Tauopathies
NFTs
Tau
Trinucleotide
Repeat Expansion
Inclusions
Expanded
PolyQ tracts
US Population Demographics
85 Years of Age or Older: 1950-2050
High
25
Millions
20
Median
15
Low
10
5
0
1950
1960
1970
1980
1990
2000
Year
2010
2020
2030
2040
2050
Synucleinopathies
• Parkinson’s disease - familial and sporadic*
• Dementia with Lewy bodies
• Multiple system atrophy
• Neurodegeneration with brain iron
accumulation-1 (formerly H-SD)
• Pure autonomic failure
• REM sleep behavior disorder
• Down syndrome*
• Alzheimer’s disease* (The most common αsynuclein brain amyloidosis!)
• * These disorders are “triple” brain amyloidoses
with tau, Aβ and α-synuclein amyloid deposits
Normal Alpha Synuclein
• An abundant low Mr synaptic protein,
present to a lesser extent in perikarya
and axons, but also in oligodendroglia
• Other members of the synuclein family
of synaptic proteins include beta- and
gamma-synuclein
• Function is unknown but may play roles
in synaptic transmission
• Is a phosphoprotein, but role of alphasynuclein phosphorylation in its normal
function is unknown
Alpha-Synuclein Mutations Cause
Familial Parkinson’s Disease
= 6 imperfect repeats of 11
amino acids with the conserved
core KTKEGV
NAC peptide (aa 61-95)
A30P
A53T
mutation mutation
H2N
COOH
Hydrophobic Middle Negatively Charged
Carboxy-terminus
Section
Mutations promote protein aggregation
and filament formation
Pathological Alpha-Synuclein
• Forms insoluble filamentous aggregates
with the properties of amyloid
• Amino acids 71-82 in the NAC domain are
the minimal, essential sequences required
for fibrilization
• Filamentous alpha-synuclein inclusions
form in neuronal perikarya, processes and
in gliaI cells
• Is abnormally phosphorylated, nitrated
and ubiquitinated
Alpha-Synuclein Pathological Inclusions
Lewy bodies
Lewy neurites
Lewy bodies
Electon microscopy
Glial cytoplasmic
inclusions
Glial cytoplasmic inclusions
Electron microscopy
Alpha-synuclein Dysfunction And
Aggregation Play Central Roles in
Mechanisms of Neurodegenerative Disease
Genetic Factors
-Synuclein
Mutations or APP, PS1, PS2
Duplications Mutations, DS
Environmental
and/or Genetic
Risk Factors
?
Synuclein Dysfunction and/or
Aggregation
Neurodegeneration
But hold on! Tau and Alpha-Synuclein Pathology
Commonly Co-occurr in Neurodegenerative
Diseases – So what does this mean?
• Diseases with tau, α-synuclein and abundant Ab
deposits
– Lewy body variant of Alzheimer’s disease
– Alzheimer’s disease
– Familial Alzheimer’s disease
– Down’s syndrome
• Diseases with tau, α-synuclein and scant/no Ab deposits
– Parkinson’s disease/Dementia with Lewy bodies
– Multiple system atrophy
– Guam ALS/PDC
– Neurodegeneration with brain iron accumulation type 1
– Some cases of PSP, CBD, and Pick’s disease
Normal Tau Proteins
• Abundant low molecular weight
microtubule (MT) associated
proteins localized mainly in axons
• Promote MT polymerization, bind
to MTs and stabilize MTs in the
polymerized state
• Normally is phosphorylated at a
range of Ser and Thr residues
• Phosphorylation negatively
regulates binding of tau to MTs
Six Human Brain Tau Isoforms Are
Generated By Alternative Splicing
SDS-PAGE
4R2N
67kDa
62kDa
1
E2 E3
E10
3R2N 1
R1
R2
R3
R1
R3
R4
59kDa
4R1N 1
R1
R2
R3
54kDa
3R1N 1
R1
R3
R4
52kDa
48kDa
4R0N 1
R1
R2
R3
3R0N 1
R1
R3
R4
441
R4
410
412
R4
381
383
R4
352
R2
PHF-Tau Proteins
• Insoluble
• Form filamentous amyloid deposits
in neuronal cell bodies/processes
and glia
• Aberrantly hyperphosphorylated at
Ser/Thr; ubiquitinated
• Unable to bind to MTs unless
dephosphorylated in vitro
Tau Mutations Cause FTDP-17 By Different Mechanisms And Aggregation Of Tau
Disrupts Axonal Transport Leading to Neurodegeneration
1
441
Exon 10
N279K D280K
G
Intron 9
D AAG
L284L
P301S P301L
S305N S305S
+3
C
TU
AC
a
c a
g
a
a
c
a
c
u
c
u
g
t
u
u/t
u
u
AAUAAGAAGCUGGAUCUU----------CCGGGAGGCGGCAG-U g
g
g
+16 +14 +13 +12
u
c
Intron 10
Mutations Impairing Mutations Promote Mutations Altering
Exon 10 Splicing
Tau Protein Function Tau Aggregation
-G272V
-D280K -P301L
-P301S -V337M
-G389R-R406W
-G272V -P301L –P301S
-V337M
-N279K
-D280K -L284L
-S305N -S305S
-Intron 10 mutations
Tau Positive Inclusions in Neurons
AD
GUAM
CBD
Pick’s
disease
FTDP17
PSP
DEM
PEG
Paired Helical Filaments (PHFs) Formed By
Tau Are Building Blocks Of NFTs In AD Brain
• Two twisting
strands with an
apparent
periodicity of
80nm and an
alternating width
between 8 and
20nm
• Molecular
composition tau
From Lee et al. Science (1991) 251, 675-8
Sarkosyl-insoluble Tau Bands
Before and After Dephosphorylation
Dephos.
72kDa
68kDa
64kDa
60kDa
•
•
•
•
•
•
-
+
-
+
-
+
67kDa
2N4R
62kDa
2N3R
59kDa
1N4R
54kDa
1N3R
52kDa
0N4R
48kDa
0N3R
AD
• FTDP-17
ALS/PDC
(DK280)
Down’s syndrome
• Pick’s disease
FTDP-17 (G272V, V337M,etc.)
GSS
Nieman-Pick disease type C
• CBD
• FTDP-17 (mutations
in I10, L284L, etc.)
• PSP
Tau Dysfunction And The Pathogenesis Of AD
And Related Neurodegenerative Tauopathies
Genetic Factors
Tau
APP, PS1, PS2
Mutations
Mutations
Perturbation of 4R/3R Ratio
Loss of Tau Function
Gain of Toxic Function
?
Environmental
Factors
?
Hyperphosphorylation
DeP-Tau
Kinases
P-Tau
Phophotases
Tau Dysfunction
Tau Aggregation/ MT Loss
Impaired Transport &
Neurodegeneration
Tau Pathology in Patients with the A53T
Alpha-Synuclein Mutation
-syn
Tau
Summary of -Synuclein
Assembly Studies
• -Synuclein readily assembles into 10
nm diameter filaments
• A53T mutation facilitates -synuclein
assembly
• b-Synuclein is incapable of
fibrillogenesis
• Residue 71-82 is required for synuclein filament assembly
HSP70 PROTECTS AGAINST ALPHASYNUCLEIN INDUCED DOPAMINERGIC
NEURON DEGENERTATION
(Auluck et al., Science 2002)
Characterization of -Synuclein Transgenic Mice
(Giasson et al., Neuron, 2002)
Abundant -synuclein Inclusions in A53T
-synuclein Transgenic Mice
SNL-4
Spinal cord
Syn 303
Spinal cord
Syn 303
Raphe
Syn 505
pons
Syn 506
Syn 303
pons
pons
SNL-4
Spinal cord
Syn 505
pons
Syn 505
locus ceruleus
SNL-4
Spinal cord
Syn 303
midbrain
Syn 505
cerebellum
Accumulation of Detergent Insoluble -synuclein
in the Spinal Cord of A53T Tg Mice
α-Synuclein Filaments can be Isolated from A53T
Transgenic Mice
Tau Pathology in the Spinal Cord
and Midbrain of A53T a-Syn Tg Mice
tau
a-syn
tau
tau
a-syn
tau
tau
overlay
Lessons From Nicoll, et al. (Nat. Med., 2003)
For Therapy Of Brain Amyloidoses
• Subtraction of Aβ from the brains of
patients with diseases having abundant
tau, alpha-synuclein & Ab pathologies
– Lewy body variant of Alzheimer’s disease
– Sporadic/Familial AD
– Down’s syndrome
• Will convert them to phenocopies of diseases
with abundant tau and/or alpha-synuclein, but
scant/no Ab pathologies
– Parkinson’s disease/Dementia with Lewy bodies
– Guam Marianna dementia/PDC
Model of Fibrilization in
Neurodegenerative Disease
^ ^
^
= -helix
= random coil
= b-pleated sheet
The Deleterious
Consequences
Of Protein Misfolding
Cell
Death
mRNA
Ribosomes
chaperone
C
Misfolded Small
Inclusions
oligomers
C
N
C
N
N
N
N
Cell
Death
Proteasome
Microtubules
More Deleterious
Consequences Of
Protein Misfolding
-synuclein
tau
vesicles
Improper trafficking
Increased abundance
Tau hyperphosphorylation
Pathological
aggregates
Five Year Delay in AD Onset Halves Prevalence & Incidence
It Takes Great A Team!
•
•
•
•
•
•
•
Mark Forman
Benoit Giasson
Makoto Higuchi
Hiro Uryu
Bin Zhang
CNDR Members
Virginia Lee
•
•
•
•
•
•
•
N. Bonini, J. Duda
J. Galvin, D. Galasko
L. Golbe, M. Grossman
H. Hurtig, T. Iwatsubo
C. Lippa, B. Miller
D. Murphy, M. Stern
Nat’l AD Coordinating
Center
• NIA Alzheimer Disease
Centers
• Penn Head Injury Center
Supported by Grants from the NIA, the Alzheimer’s
Association, Michael J. Fox Foundation and the Families
of our Patients
DISCLAIMER
If you attended to the content of this lecture,
you may have participated in effortful mental
activity, and this may reduce your risk for
dementia. * However, this lecture is not
intended as a therapeutic intervention and
there is no guarantee that this lecture has
therapeutic benefit.
* Wilson et al. JAMA 287:742-748, 2003;
Verghese et al. NEJM, 34:2508-2516, 2003