Académique Documents
Professionnel Documents
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Keywords
chaperone-based therapeutic approaches;
chemical and pharmacological chaperones;
molecular chaperones; protein
conformational diseases; protein misfolding
and aggregation
Correspondence
T. K. Chaudhuri, Department of Biochemical
Engineering and Biotechnology, Indian
Institute of Technology Delhi, Hauz Khas,
New Delhi 110016, India
Fax: +91 11 2658 2282
Tel: +91 11 2659 1012
E-mail: tapan@dbeb.iitd.ac.in
(Received 3 January 2006, revised 10 February 2006, accepted 14 February 2006)
doi:10.1111/j.1742-4658.2006.05181.x
A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the
primary cause of Alzheimers disease, Parkinsons disease, Huntingtons
disease, CreutzfeldtJakob disease, cystic brosis, Gauchers disease and
many other degenerative and neurodegenerative disorders. Cellular molecular chaperones, which are ubiquitous, stress-induced proteins, and newly
found chemical and pharmacological chaperones have been found to be
effective in preventing misfolding of different disease-causing proteins,
essentially reducing the severity of several neurodegenerative disorders and
many other protein-misfolding diseases. In this review, we discuss the probable mechanisms of several protein-misfolding diseases in humans, as well
as therapeutic approaches for countering them. The role of molecular,
chemical and pharmacological chaperones in suppressing the effect of protein misfolding-induced consequences in humans is explained in detail.
Functional aspects of the different types of chaperones suggest their uses as
potential therapeutic agents against different types of degenerative diseases,
including neurodegenerative disorders.
Abbreviations
AD, Alzheimers disease; ADH, antidiuretic hormone; AVP, arginine vasopressin; BSE, bovine spongiform encephalopathy; CF, cystic fibrosis;
CFTR, cystic fibrosis transmembrane regulator; CJD, CreutzfeldtJacob disease; DMSO, dimethyl sulfoxide; ER, endoplasmic reticulum;
FAP, familial amyloid polyneuropathy; GD, Gauchers disease; GSH-MEE, glutathione monoethyl ester; HbS, hemoglobin S; HD,
Huntingtons disease; HSP, heat shock protein; MCD, mad cow disease; MJD, Machado-Joseph disease; NAC, N-acetyl-L-cysteine;
NDI, nephrogenic diabetes insipidus; NOV, N-octyl-h-valienamine; PCD, protein conformational disease; PD, Parkinsons disease; PGD,
polyglutamine disease; RP, retinitis pigmentosa; SCA, spinocerebeller ataxia; SSA, senile systemic amyloidosis; TMAO, trimethylamineN-oxide; UPP, ubiquitin proteasome pathway.
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Table 1. Mutation observed in different disease causing proteins. CF, cystic fibrosis; NDI, nephrogenic diabetes insipidus; PD, Parkinsons
disease; AD, Alzheimers disease; HD, Huntingtons disease; SCA, spinocerebellar ataxia.
Disease
Proteins affected
Ref.
CF
a-Antitrypsin deficiency
NDI
CFTR
a-Antitrypsin
Aquaporin-2 V2asopressin
[20]
[21]
[22]
Fabry
Cancer
1
a-Galactosidase A
p-53
DF508
D342K
T126M, A147T, R187C
R187C D6264, L59P, L83Q,
Y128S, S16L, A294P, P322H, R337X
R301Q, Q279E
R175, G245, R248, R249,
R273 and R282
A53T, A30P
AD 1, AD 2, AD 3, AD 4 Tau, preselinin 1 and 2,
a-macroglobulin
HD
SCA
PD
AD
aHD
SCA
a-synuclein
Amyloid precursor protein
Huntingtin
Ataxin
[23]
[24]
[16]
[25]
[25]
[25]
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Protein-misfolding diseases
-helix
-helix
-sheet
A
-helix
-sheet
B
Fig. 1. During amyloid formation most of the a-helical structures in the polypeptide chain of a native protein are converted into b-pleated
sheets. (A) Native polypeptide chain composed of mainly a-helical secondary structure. (B) Misfolding causes conversion of a-helical
structure to b-pleated sheets and (C) final misfolded structure of polypeptide chain contains mostly b-pleated sheets.
1334
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Protein-misfolding diseases
I: Dimerization
Monomer
II: Oligomerization
Dimer
Monomer
Tetramer: Forming
aggregate
Fig. 2. Protein oligomerization. Misfolded monomers forming aggregate through intermolecular hydrogen bonding interaction leading to
b-sheet formation.
tau. NFTs are aggregations of the microtubular protein tau, which are found to be hyperphosphorylated
in the neuronal cells of AD patients. Although, tau
polymer formation is a hallmark of other degenerative
disorders, such as corticobasal degeneration, progressive supranuclear palsy and pick disease [49], all differ
from AD in that they lack Ab plaque deposition [50].
In contrast to AD, it is believed that in PD, protein
accumulates in the intracellular space [51]. PD is the
second most common, late-onset neurodegenerative
disorder, and is characterized by muscular rigidity,
postural instability and resting tremor. It is a slow progressive disorder and the pathology of PD involves the
degeneration of dopaminergic neurons in the substantia nigra and the deposition of intracytoplasmic inclusion bodies called Lewy bodies in brain cells. The
exact mechanism by which these cells are lost is not
known. Heritable forms of PD are caused by gene
mutations. To date, three genes encoding a-synuclein,
parkin and ubiquitin C-terminal hydrolase L1 protein
have been shown to be associated with familial forms
of PD [52]. All three proteins are present in Lewy bodies in sporadic PD [53] and in dementia with Lewy
bodies [54]. Two missense mutations in the gene encoding a-synuclein are linked to dominantly inherited
PD, thereby directly implicating a-synuclein in the
pathogenesis of the disease. Recent studies suggest that
the intracellular accumulation of a-synuclein [55] leads
to mitochondrial dysfunction [56], oxidative stress
[57,58] and caspase degradation [59] accentuated by
mutations associated with familial parkinsonism
[60,61].
The prion protein, which is thought to be responsible for causing a disease in cattle, called bovine
spongiform encephalopathy (BSE, or mad cow disease), and a disease in humans, called variant Creutz-
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Protein-misfolding diseases
Normal cellular
prion protein are
infected by Scrapie
prion molecule
Newly converted
prions again infect
other normal
cellular prions
PrPSc
PrPSc
PrPSc
PrPSc
PrPC
PrPC
PrPC
PrPC
PrPC
(i)
PrPSc
PrPSc
PrPSc
PrPSc
PrPSc
PrPC
(ii)
(iii)
Fig. 3. Propagation of PrPSc takes place through the interaction of PrPSc with normal cellular protein PrPC. Binding between PrPSc and PrPC
induces conformational change in PrPC protein that results in the formation of PrPSc, which form aggregates through intermolecular association. (i) Transmissible isoform of one prion protein molecule infects other normal cellular prion molecules. (ii) Infection causes induction in
conformation of normal prions that converts them to transmissible prion molecules, which again start infecting other normal prion molecules.
(iii) All the cellular normal prions are transformed into disease causing scrapie prion proteins.
Table 2. Neurodegenerative diseases caused by repetition of CAG codon which encodes glutamine in the polypeptide chain of the responsible proteins.
Disorder
Huntington
Spinal and bulbar
muscular atrophy
Spinocerebellar ataxia
Type 1
Type 2
Type 3
Type 6
Type 7
DentatorubropallidoLuysian atrophy
Protein
responsible
Normal No.
of repeats
No. repeats in
mutant protein
Ref.
Huntingtin
Androgen receptor
1134
1133
40120
4062
[45,7578]
[79]
Ataxin 1
Ataxin 2
Ataxin 3
Ataxin 6
Ataxin 7
Atrophin 1
2536
1524
1336
416
735
725
4181
3559
6282
2127
37130
4985
[80]
[81]
[82,83]
[84]
[85]
[86]
product, now containing an usually long string of glutamine residues, appears to misfold and form large
detergent-insoluble aggregates within the nucleus or
cytoplasm, thereby leading to the eventual demise of
the effected neuron [5]. To date eight different inherited neurodegenerative diseases (Table 2) have been
found to be due to expansion of glutamine repeats in
the affected proteins. HD is the most frequent of
them.
MachadoJoseph disease spinocerebellar ataxia-3
(MJD SCA-3) is another inherited neurodegenerative
disorder caused by expansion of the polyglutamine
stretch in the MJD gene-encoded protein ataxin-3. The
truncated form of mutated ataxin-3 causes aggregation
and cell death in vitro and in vivo. In vitro cellular
models and transgenic animals have been created and
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Table 3. Classification of amyloidoses and name of precursor proteins and nomenclature [109a]. Amyloidoses that affect central nervous
system are not considered here. G, generalized; L, localized.
Precursor protein
Designation
Diffusion
Syndrome
AL
AH
ATTR
Ab2M
G, L
G, L
G
G
ApoA-I
ApoA-II
ApoA-IV
Alys
AANF
Ains
Acys
IAPP
G, L
G
G
L
L
L
L
AGel
AFib
Familial
Nephropathy, hyperpathy
Amyloidoses
In all the above cases either misfolded proteins form
brillar aggregates which become toxic and lead to cell
death (all neurodegenrative diseases) or, in other category of disease, misfolded proteins are directed to the
proteasome pathway for degradation (proteolysis), and
protein deciency causes the disease. In a third case,
even if the brils themselves are not toxic, the ready
autolinkage of proteins and polypeptides by b-strand
bonding involves risks of further linkage to give insoluble macrostructures [105,106], these macrostructures
are deposited in the tissues and cause disease (Table 3)
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Protein-misfolding diseases
Table 4. Proteins involved in different human diseases caused by misfolding, aggregation and trafficking [5,26].
Proteins
Disease
Cause
Ref.
Hemoglobin
CFTR protein
Prion protein (PrP)
S
F
Huntingtin
b-amyloid protein
b-glucosidase
a-Synuclein
V2 vasopressin receptor
Transthyretin
M
Rhodopsin
aB1B-Antitrypsin
a-Galactosidase
P53
Aggregation
Trafficking
Aggregation
[96]
[89]
[110]
Aggregation
Aggregation
Trafficking
Aggregation
Trafficking
Aggregation
[45,7578]
[46]
[103,105]
[51]
[97,98]
[6774]
Trafficking
Trafficking aggregation
Trafficking
Trafficking
[99]
[90]
[101,102]
[92]
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DNA
Ribosome
RNA
CHIP
Ubiquitin
conjugation
(A)
Native
Porotein
Misfolded
protein
(B)
ATP
Ubiquitin
E1
E3
E2
(C)
Impaired
ubiquiti n
Misfolded
protein
(D)
(L)
(M)
Ubiquitinated
protein
Aggregate/Fibrillar
amyloid
(E)
(F)
(K)
Partially
folded
protein
26S
P ro te o s o m e
(J)
(I)
impaired
proteasome
(O)
(N)
Hsp60
Ubiquitin
(H)
Hsp104
Hsp90
Hsp40
Gain of
toxicity
Hsp70
E1
E2
E3
Misfolded
protein
(G)
Degraded
protein
Amyloidoses
(Familial amyloid
neuropathy)
Cause several neurodegenerative
diseases and lead cell demise like
Alzheimer disease, Parkinson disease
Fig. 4. The fate of cellular misfolded protein is shown. (A) Nascent polypeptide chain is converted into folded protein. (B) Polypetide chain
reaches misfolded structure. (C) Native protein molecule is converted into misfolded structure due to specific mutation or cellular stress. (D)
In the first step Hsp 40 70 90 facilitate to direct them to the proteasomal pathway and the second step is ubiquitination of misfolded protein assisted by E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme) & E3 (ubiquitin ligase). (E) Due to the damage of ubiquitin
enzymes, misfolded protein is directed to the aggregation pathway. (F) Misfolded protein enters into the proteasome system with the help
of ubiquitin complex. (G) Proteasomes action degrades misfolded protein into small peptides and ubiquitin is regenerated. (H) Impaired proteasome system couldnt degrade misfolded protein. (I, J) The misfolded protein forms aggregate. (K) Cellular Hsp104 disaggregates the
compact aggregates and develop partially folded monomer with the assistance of Hsp70. (L) Partially folded protein is converted into native
protein by the action of Hsp60 chaperones. (M) Hsp104 and Hsp70 chaperones can directly convert compact aggregate into native monomeric protein. (N) Aggregates or fibrillar amyloid may further interact each other to form plaque like structure and accumulates in the different cellular space and becomes toxic and this toxicity formation cause amyloidosis class of disorders. (O) Non-toxic matured amyloid cause
Amyloidoses type disorders.
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Protein-misfolding diseases
Step1
Step2
Step3
ATP
ATP
ATP
ClpB
Matured
aggregate
DnaK/DnaJ/
GrpE
Loose aggregate
GroEL/
GroES
Partially
folded chain
Native
Fig. 5. Protein disaggregation process in E.coli by chaperones [121]. Step1: ClpB chaperone preproceses the aggregate and produces a
loose structure having more hydrophobic surfaces (HS) exposed to the solvent. Step2: Dnak binds to those newly exposed HS along with
co-chaperones DnaJ and GrpE, disaggregates the loose aggregates and refolds them partially. Step3: GroEL and GroES assist final refolding
from monomeric partially folded form to native state.
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Protein-misfolding diseases
Table 5. Mutational effect in human proteins corrected by molecular, chemical and pharmacological chaperones [5]. HD, Huntingtons disease; MJD, Machado-Joseph disease; AD, Alzheimers disease; PD, Parkinsons disease; CF, cystic fibrosis; NDI, nephrogenic diabetes
insipidus; CJD, Creuzfeld-Jacob diease; GD, Gauchers disease.
Type of chaperone
Chaperone name
Disease
Molecular
Chemical
Pharmacological
strate molecules resulted in mature and active P-glycoprotein, and based on the same type of approach,
other similar molecules were found which are collectively named as pharmacological chaperones. Their use
is needed only at the micro molar level in the cell to
prevent misfolding of mutant proteins.
Pharmacological chaperones have proved very
effective in rescuing a few receptor proteins from proteasomal degradation. Pharmacological ligands act by
binding to specic conformations of receptor proteins
and stabilizing them. Selective VB2B receptor antagonists, which are retained in the ER and are responsible
for NDI, were assessed to reveal whether they facilitate
the folding of mutant VB2B receptor protein. Biosynthesis of mutant VB2B receptors was monitored in the
presence of the selective V2 receptor nonpeptide antagonist SR121463A. Morello et al. [144] proposed a
model for the mode of action of pharmacological
chaperones. Small nonpeptide VB2B receptor antagonists permeate the cell and bind to unstable folding
intermediates of the mutant receptors; this would stabilize a conformation of the receptor that allows its
release from the ER quality control system. The stabilized receptor proteins would then be targeted to the
cell surface where they bind AVP and promote signal
transduction upon dissociation from the antagonist.
These antagonists are VB2B specic and have the same
function as a chaperone, hence they are referred to as
pharmacological chaperones.
Loo & Clarke functionally characterized articial mutations of the multidrug resistance 1 gene (ABCB1), which
codes for P-glycoprotein 1, an energy-dependent transporter at the plasma membrane that interacts with a
wide variety of cytotoxic agents [126]. Morello et al.
[144] proved that selective V2 receptor antagonists
(SR121463A, VPA985) can permeate the cell surface
and facilitate the folding of mutant V2 receptors which
are retained in the ER and cause NDI.
Different molecular, chemical and pharmacological
chaperones, which have been already studied experi-
Conclusions
From the discussion on the mechanisms of different
protein misfolding disorders, it is clear that a nascent
polypeptide chain can become misfolded due to a specic gene mutation, which takes place in almost all
familial neurodegenerative diseases, or a matured
native protein can also achieve a misfolded conformation inside the cell, an example is the cause of prion
disease. The fates of these misfolded proteins in various disorders are different, in one class of diseases
misfolded proteins interact further with each other
through intermolecular interaction and form structured
aggregates thus gaining toxicity. Neurodegenerative
disorders are good examples of this specic pathway.
It might be that the proteasome pathway is not efcient enough to degrade these misfolded proteins prior
to aggregation because of impairment of the UPS. In
another case, misfolded proteins are directed to the
UPP with the help of many other chaperones in addition to ubiquitins, and are consequently degraded by
the action of proteasome. Hence these proteins cannot
be secreted from the ER, but are degraded and
their disappearance from the specic site inside the
cell where they function causes disease. Good
examples of this are CF and a-antitrypsin deciency
disorders.
Whatever the reason for a protein not achieving its
functional form, it is the conformational defect that
leads to disease. Therapy should therefore aim to inhibit and or reverse conformational changes in the
protein molecules responsible. In most PCDs the misfolded protein is rich in b sheet, and therapy
should involve designing a peptide to prevent and
reverse b-sheet formation. It might be possible to correct these diseases by persuading the misfolded proteins
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Protein-misfolding diseases
Table 6. Mutations rescued by chemical and pharmacological chaperones. CF, cystic fibrosis; NDI, nephrogenic diabetes insipidus.
Disease
Protein
CF
a-Antitrypsin deficiency
NDI
CFTR
a-Antitrypsin
Aquaporin-2
NDI
Aquaporin-2
V2 vasopressin
Fabry
Cancer
a-Galactosidase A
p53
Mutations
recovered
DF508
D342K
T126M,
A147t, r187c
T126M, A147T,
R187C,R187C
D6264,l59p, l83q,
Y128S, S16L,
A294P,
P322H, R337X
R301Q, Q279E
L173A, L175S,
V249S, M273H
Agents used
Ref.
[20]
[21]
[22]
SR121463A, VPA985
[146]
1-Deoxy galactonojirimycin
CP31398, CP257042
[23]
[24]
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