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Acta Biochim Biophys |
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doi:10.1111/j.1745-7270.2008.00441.x |
Quality control of the
proteins associated with neurodegenerative diseases
Xuechao Gao and Hongyu Hu*
State Key
Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai
Institutes for Biological Sciences, the Chinese Academy of Sciences, Shanghai
200031, China
Received: May 15,
2008
Accepted: June 5,
2008
This work was
supported by a grant from the National Basic Research Program of China
(2006CB910305)
*Corresponding
author: Tel, 86-21-54921121; Fax, 86-21-54921011; E-mail, [email protected]
Most
neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s
disease and other polyglutamine diseases are associated with degeneration and
death of specific neuronal populations due to misfolding or aggregation of
certain proteins. These aggregates often contain ubiquitin that is the signal
for proteolysis by the ubiquitin-proteasome system, and chaperone proteins that
are involved in the assistance of protein folding. Here we review the role of
protein quality control systems in the pathogenesis of neurodegenerative
diseases, and aim to learn more from the cooperation between molecular
chaperones and ubiquitin-proteasome system responding to cellular protein
aggregates, in order to find molecular targets for therapeutic intervention.
Keywords quality
control; protein misfolding; molecular chaperones; ubiquitin-proteasome
system; neurodegenerative disease
Protein folding is a very important post-translational process in
cells. Newly synthesized proteins must fold into their correct three-dimensional
structures and maintain these native states throughout their lifetime with the
help of molecular chaperones and other cofactors. However, many cellular events
such as genetic mutation, biosynthetic errors, or the absence of a necessary post-translational
binding partner can result in protein misfolding. Cellular stresses such as
chemical or temperature perturbation can also unfold or misfold proteins.
Misfolding of a protein leads to the exposure of hydrophobic patches, which may
cause protein aggregation in the aqueous cellular environment. This may result
in the formation of toxic protein precipitates, inactivation of functional
proteins, and ultimately cause cell death.
Neurodegenerative diseases are the nerve disorders caused by gradual
loss of neurons in patient brains. Changes in these neurons result in abnormal
cellular function, and eventually bringing about cell death. These diseases are
now known to result, directly or indirectly, from aberrant protein folding and
aggregation (Table 1). Classic examples include Alzheimer‘s disease
(AD), Parkinson‘s disease (PD), Huntington‘s disease (HD) and other polyglutamine
(polyQ)-expanded diseases. The hallmark of a large group of neurodegenerative
diseases is the presence of cytosolic, nuclear or extracellular protein
aggregates, which are often ubiquitinated and may be associated with
chaperones [1]. The misfolded proteins or aggregates are apparently tagged for
refolding by molecular chaperones or degradation by ubiquitin-proteasome system
(UPS). In a normal cell, this protein quality control system is well organized
and self-regulated for the whole life; however, these protein aggregates in an
abnormal cell fail to be targeted to or degraded by the proteasome. Here we
review the protein quality control components in the pathology of neurodegenerative
diseases, and the molecular mechanisms underlying how the chaperones cooperate
with the UPS in safeguarding cellular proteins and eliminating the degenerated
proteins.
Molecular Chaperones: the
First Line of Defense against Protein Misfolding and Aggregation
Molecular chaperones, most of which belong to heat shock proteins
(HSP), are the first line of defense against protein misfolding and
aggregation. Chaperones bind to unfolded stretches in proteins and keep them in
a folding-competent state while preventing aggregation. In addition, they can
help dissolve aggregates and target misfolded proteins for degradation. Recent
research also indicates that molecular chaperones can assist correct folding
not only of wild-type proteins but also of some mutant proteins [2,3]. Of
particular interest for the formation of aggregates in eukaryotes is the
70 kDa heat shock protein (Hsp70) class of chaperones. Hsp70 binds to
small hydrophobic stretches in proteins, in cooperation with a cochaperone of
the Hsp40 family. Binding to the substrate requires ATP hydrolysis and with the
help of a nucleotide-exchange factor (NEF) or/and other specific regulators.
The ADP molecule is exchanged for a new ATP, which will be hydrolyzed in order
to release the substrate [4]. Additional Hsp70 cochaperones have been
identified that modulate the various activities of Hsp70s during specialized
cellular functions in eukaryotes [5]. Members of the 90 kDa heat shock protein
(Hsp90) family act downstream of the Hsp70/Hsp40-chaperone system and play an
important role in conformational protein regulation and cell signaling [4]. The
small heat shock proteins (sHsps) are a ubiquitous class of ATP-independent
chaperones. They have subunit molecular masses ranging from ~15 to ~40 kDa and share
a C-terminal core domain of about 100 residues, thought to be involved in the
formation of dynamic higher order oligomers of up to 50 subunits. These large
structures were suggested to reorganize into smaller, active complexes when a
cell is exposed to stress [6].
Many studies have shown that misfolded proteins or their aggregates
are associated with molecular chaperones, most prominently those of the Hsp70
family. For instance, Hsp70 and Hsp40 chaperones were shown to colocalize with
the aggregates formed by polyQ-expanded proteins, such as huntingtin (Htt) and
ataxin-3, in cellular models and in disease tissue [7,8], as well as with Lewy
bodies in the affected brain tissue of PD patients [9]. Additionally, Hsp70 and
Hsp16 chaperones may interact with intracellular amyloid b peptide (Ab) [10]. The
association of misfolded protein or aggregates with chaperones implies that the
cellular quality control machinery is activated in an attempt to prevent the
accumulation of misfolded proteins. Consistent with this notion, the presence
of aggregates in cells is known to trigger the heat-shock response, which
induces the expression of Hsps [11].
More than co-localization, a growing body of evidence suggests that
molecular chaperones modulate the aggregation of a variety of neurodegenerative
disease-associated proteins, including polyQ-containing proteins, Ab peptide, a-synuclein (a-Syn), and prion
protein (PrP) [12]. In the case of polyQ proteins, the expression of chaperones
Hsp70 and Hsp40 diverts the polyQ aggregation pathway from formation of sodium
dodecyl sulfate (SDS)-insoluble fibrils to formation of amorphous and less
stable (SDS-soluble) aggregates. Fluorescence resonance energy transfer (FRET)
experiments suggest that toxic oligomerization of mutant Htt begins with an
intra-molecular structural rearrangement of monomeric Htt. Hsp70 and Hsp40
inhibit this intra-molecular rearrangement, presumably preventing monomeric Htt
from achieving the b-sheet conformation necessary for the formation of mature fibrils.
Under these conditions, the formation of soluble, amorphous aggregates would
instead be favored for the cell survival. Co-transfection of mutant ataxin-1
with human DnaJ 2 (Hdj2) results in a significant reduction in aggregate
formation. On the other hand, when the mutant ataxin-3, a causal protein of
spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD), is
transfected into COS7 or PC12 cells, it forms large nuclear aggregates. In this
case, both Hdj1/Hsp40 and Hdj2 could suppress the aggregate formation [13].
Hsp70 could also inhibit a-Syn fibril formation through preferential binding to prefibrillar
species to change the characteristics of toxic a-Syn aggregates [14]. These
studies suggest that molecular chaperones are capable of modulating the
conformation of the disease-related proteins, which in some circumstances may
prevent the toxic accumulation of misfolded species.
In agreement with the chaperone mechanism described above, several
studies have reported a reduction in cellular toxicity upon expression of
chaperones (Hsp70, Hsp40) in aggregation-associated disease models [2,15]. For
example, in a Drosophila melanogaster model of PD, directed expression
of the molecular chaperone Hsp70 prevents the neuronal loss caused by a-Syn [15].
Likewise, in a yeast model of HD, expression of Hsp70 and Hsp40 reduces the
toxicity associated with expression of mutant Htt, by preventing its aberrant
interaction with an essential polyQ-containing transcription factor [2].
Moreover, the mutant ataxin-3-mediated neurodegeneration is suppressed by Hsp70
in a transgenic fruit fly model [13]. These findings support a general concept
that chaperone action is a crucial aspect in protecting against the otherwise
damaging consequences of protein misfolding and aggregation.
Ubiquitin-proteasome System:
the Second Line of Defense against Protein Misfolding and Aggregation
The ubiquitin-proteasome system (UPS) is now believed to be the
principal system for turnover of short-lived, misfolded or truncated proteins
in eukaryotic cells. Targeted proteins must become conjugated to a
poly-ubiquitin chain to be recognized by the proteasome, including a battery
of steps orchestrated by many enzymes and protein factors. Ubiquitin
conjugation or ubiquitination is a highly ordered process, in which an
ubiquitin-activating enzyme (E1) first activates and transfers ubiquitin to an
ubiquitin-conjugating enzyme (E2) that then acts in concert with an E3 ligase
to transfer ubiquitin to a lysine residue on the target substrate. A chain of
at least four ubiquitin moieties is required for substrate recognition by the
26S proteasome complex [16].
Cellular ubiquitin-containing inclusions are a characteristic
feature of major neurodegenerative diseases, suggesting an involvement of the
ubiquitin-proteasome system. The first indication that ubiquitin-mediated
proteolysis may play a role in the pathogenesis of neurodegenerative disorders came
in the late 1980s, with the finding that ubiquitin immunoreactivity is
detected in the cellular inclusions, which characterize a number of the major
human degenerative diseases, such as
neurofibrillary tangle in AD, Lewy bodies in PD and nuclear inclusions
in HD [17].
There is growing evidence for proteasome involvement in
neurodegenerative diseases. In both diseased tissue and in vitro model,
the 26S proteasome complex redistributes into the cellular aggregates. In the
neurons from SCA3/MJD brain, the proteasome localizes in the intranuclear
inclusions that contain the mutant ataxin-3 [18]. While in transfected cells,
the proteasome redistributes into the inclusions formed by expanded polyQ
proteins. On the other hand, inhibition of proteasome causes an increase in
aggregate formation with a repeat length-dependent manner, implying that the
proteasome plays a direct role in suppressing polyQ aggregation in disease
[18]. Moreover, the proteasomal 20S subunit is redistributed to the polyQ
aggregates in HD 60Q and HD 150Q cell lines and in the brain of HD exon 1
transgenic mouse models. Proteasome inhibitor dramatically increases the rate
of aggregate formation caused by N-terminal Htt protein with 60Q repeats, but
not by the protein with 150Q [19]. Interestingly, a massive accumulation of
ubiquitinated derivatives was observed in Htt protein containing 150Q but not
60Q or 16Q [19]. These results strongly suggest that the expanded polyQ
proteins are degraded by proteasome, but the rate of degradation is inversely
proportional to the repeat length. Overexpression of a number of
neurodegenerative disease-associated proteins including presenilin-1, parkin
and Htt that are associated with AD, PD and HD, respectively, in
proteasome-inhibited mammalian cells leads to inclusion formation
[5,10,12,15]. Moreover, the disease-associated mutant proteins readily form
aggregates without the need for proteasome inhibition [20], and a systemic
administration of a proteasome inhibitor can induce a Parkinson-like phenotype
in rats, developing a progressive parkinsonism with bradykinesia, rigidity,
tremor, and an abnormal posture, which improved with apomorphine treatment
[21].
How are misfolded proteins recognized by the ubiquitin-proteasome
system in neurodegenerative diseases? Up to now, many E2 conjugation enzymes
and E3 ligases have been identified as proteins that are either directly
responsible for, or associated with specific neurodegenerative diseases.
Ubiquitin conjugating enzymes (Ubc) have been identified that affect polyQ
aggregates in Caenorhabditis elegans. Specifically, RNA interference
(RNAi) knockdown of ubc-2 or ubc-22 causes a significant increase in the size
of aggregates as well as a reduction in aggregate number. In contrast, RNAi of
ubc-1, ubc-13, or uev-1 leads to a reduction of aggregate size and eliminates
ubiquitin and proteasome localization to aggregates. In cultured human cells,
knockdown of human homologs of these Ubcs (Ube2A, UbcH5b, and E2-25K) causes
similar effects, indicating a conserved role for ubiquitination in polyQ
protein aggregation [22]. Mutant product of presenilin can increase Ab deposits and
subsequent plague formation, is also degraded via the UPS by an E3 SKP1-CUL1-F-box
protein (SCF) complex containing the F-box and WD repeat domain containing 7
(FBXW7) [23]. Co-expression of FBXW7 and amyloid precursor protein (APP) can
increase presenilin ubiquitination and elevate Ab production.
Parkin is a PD-related E3 ligase; it contains both a really
interested new gene (RING) domain with E3 ligase activity and an
ubiquitin-like (UbL) domain [24]. Parkin can promote ubiquitination of three
PD-associated proteins, a-Syn, parkin-associated endothelin-receptor-like receptor (Pael-R)
and synphilin-1 (Sph1) both in vitro and in vivo [25], and
ubiquitination and degradation of an expanded polyQ protein [26].
Overexpression of parkin reduces aggregation and cytotoxicity of an expanded
polyQ ataxin-3 fragment [26]. Parkin forms a complex with the expanded polyQ
protein, Hsp70 and the proteasome, which may be important for the elimination
of the expanded polyQ protein. Hsp70 enhances parkin binding and ubiquitination
of the expanded polyQ protein in vitro, suggesting that Hsp70 may help
to recruit misfolded proteins as substrates for the ubiquitin E3 ligase
activity of parkin. Parkin may function to relieve endoplasmic reticulum
stress by preserving proteasome activity in the presence of misfolded proteins.
Loss of parkin function and the resulting proteasomal impairment may
contribute to the accumulation of toxic aberrant proteins in neurodegenerative
diseases including PD.
Other E3 ligases may have a significant role in PD pathology. For example,
the U-box E4 ligase carboxyl terminus of Hsp70 interacting protein (CHIP)
interacts with Pael-R and enhances ubiquitination of Pael-R by parkin [27].
Additionally, the RING E3 ligases dorfin and Siah-1 are both capable of
targeting an a-Syn partner Sph1 for degradation [28,29]. Dorfin is another
mammalian E3 ligase implicated in quality control of protein misfolding. Like
parkin containing two RING domains, dorfin associates with and selectively
ubiquitinates mutant but not wild-type superoxide dismutase 1 (SOD1) [30]. It
colocalizes with SOD1 inclusions in transgenic mice expressing an aggregation-prone
SOD1 mutant and with Lewy bodies in PD brains. Overexpression of dorfin
increases the viability of cells that express aggregation-prone SOD1; it also
promotes ubiquitination of the parkin substrate Sph1 in cultured cells [29].
However, contrary to parkin, dorfin can associate with its known substrates
without an obvious link to Hsp70 or other chaperones.
It is unclear whether proteins with an expanded polyQ tract are good
proteasome substrates. Htt interacts with the human ubiquitin-conjugating
enzyme E2-25K, which requires the polyQ domain. As previously described, parkin
also colocalizes with mutant Htt aggregates in HD mice and human brains, and
overexpression of parkin enhances the clearance of the mutant proteins. These
results suggest that Htt may be a proteasome substrate. Consistent with this,
proteasome inhibitors such as lactacystin and epoxomycin prevent clearance of
mutant Htt in a conditional HD mouse model or cell models after its expression
is stopped [31].
Other studies by confocal and immunoelectron microscopies find that
ubiquitin-associating protein sequestosome-1/p62 colocalizes to Tau aggregates
isolated from AD brain, along with an E3 ubiquitin ligase TNF receptor-associated
factor 6 (TRAF6). Tau is a substrate of TRAF6, and p62 interacts with
K63-polyubiquitinated tau through its ubiquitin-associated (UBA) domain and
shuttles poly-ubiquitinated tau for proteasomal degradation [32].
Cooperation between Molecular
Chaperones and the Ubiquitin-proteasome System in Neurodegenerative Diseases
Protein quality control is an integral process in eukaryotic cells.
Molecular chaperones and UPS may not work alone all of the time; instead, they
work cooperatively. For instance, molecular mechanisms underlying the sorting
process rely on a cooperation of chaperone machineries and ubiquitin-chain
recognition factors [33].
A function for chaperones in targeting misfolded proteins for degradation
has been established in various ways. For example, overexpression of Hsp70 and
Hsp40 increases the proteasome-mediated degradation of a-Syn and polyQ-expanded
proteins [34]. The identification of E3 ligases and cochaperones that
physically link chaperones to the UPS further supports the idea of direct
communication between the folding and degradation machineries. A hallmark of
these emerging families of modular proteins is the presence of a combination of
chaperone-interacting domains and the domains that function in the UPS (Fig.
1).
Among the cofactors, CHIP is a well defined linker between
chaperones and UPS. CHIP contains three chaperone-interacting
tetratricopeptide repeat (TPR) domains at its N-terminus that confer binding
to Hsp70 and Hsp90, and a U-box domain with E3/E4 ligase activity at the
C-terminus [35]. The emerging role of CHIP in protein triage decision-making
would imply that this unique ubiquitin ligase is intimately involved in the
mechanism of Hsp-mediated degradation of mutant Htt and ataxins. CHIP
associates with and ubiquitinates mutated forms of both Htt and ataxin-3 to
prevent cytotoxicity [35]. When CHIP overexpression is accompanied by Hsp70
overexpression, removal of these mutants is further enhanced. In addition, CHIP
is a component of Lewy bodies in human brains, where it colocalizes with a-Syn and Hsp70
[36]. In a cell culture model, endogenous CHIP colocalizes with a-Syn and Hsp70
in intracellular inclusions, and overexpression of CHIP inhibits a-Syn inclusion
formation and reduces a-Syn level by its TPR domain [36]. Furthermore, a-Syn, Sph1 and
Hsp70 all co-immunoprecipitate with CHIP, raising the possibility of a direct a-Syn-CHIP
interaction. Together with Hsp70, CHIP not only has a unique binding affinity
for aberrant tau species, but is also responsible for its ubiquitination [37].
The isolated Tau protein from AD brain is poly-ubiquitinated at lysine residues
within the microtubule-binding domain, the same region as the CHIP-binding
region. The study from CHIP-knockout mice also indicates that CHIP is required
to ubiquitinate aberrant phospho-tau species specifically and to target them
for proteasomal degradation [38]. The fact that the TPR domain of CHIP is
required for the effects on the morphology and number of inclusions,
proteasomal degradation as well as direct interaction of CHIP with Hsp70
implicates a cooperation of CHIP and Hsp70 in the processes of disease
development.
As an E3 ligase, parkin can also bind to and cooperate with CHIP and
Hsp70, for overexpression of CHIP enhances the ubiquitin ligase activity of
parkin towards the PD-associated receptor Pael-R [27]. As with CHIP, parkin
also binds to polyQ-expanded Htt in vitro and localizes to Htt
inclusions in the brains of HD patients [26]. Furthermore, overexpression of
parkin in cultured cells improves clearance of polyQ-expanded proteins and
increases the survival rate of these cells [26]. Conversely, BAG5
(Bcl-2-associated athanogene 5), an inhibitor of both parkin and Hsp70,
accelerates neuronal degeneration in rat brains [39]. Parkin may also shuttle
certain aggregation-prone substrates to the proteasome, because it interacts
with the 26S proteasome, presumably via its UbL domain [26]. Thus, similar to
CHIP, parkin may link Hsp70-bound substrates and the proteasome while it also
acts as an E3 ligase.
The exact mechanism of the delivery of poly-ubiquitinated cargo to
the 26S proteasome is not fully elucidated yet, but it is clear that proteins
like Rad23, Dsk2 and P97/CDC48 are involved in escorting the poly-ubiquitinated
proteins to the proteasome [40]. BAG1 is the first identified member of the
BAG protein family, which consists of at least six different members in mammals
to date [41]. The BAG domain of BAG1 isoforms can modulate the chaperone
activity of Hsc70 and Hsp70 in the mammalian cytosol and nucleus. Remarkably,
The BAG1 isoforms resemble the Rad23 protein, which possesses a similar UbL
domain at its N-terminus and uses this domain to bind to the proteasome in a
stable manner [42]. Following immunoprecipitation of BAG1 isoforms from HeLa
cells, the C-8 subunit, a component of the 20S catalytic core of the
proteolytic complex, and the S-1 subunit of the regulatory particle of the
proteasome were found in association with the chaperone cofactor. The present
research reveals a role of BAG1 as a physical link between the Hsc70/Hsp70
chaperone and the proteasome. In fact, targeting of BAG1 to the proteasome
promotes an association of the chaperones with the proteolytic complex both in
vitro and in vivo [43].
Homo sapiens DnaJ1 (HSJ1) protein,
another cochaperone, has been identified as a neuronal shuttling factor for
ubiquitinated proteins [44]. HSJ1 combines a J-domain that stimulates substrate
loading onto the Hsp70 chaperone with ubiquitin-interacting motifs (UIMs)
involved in binding ubiquitinated chaperone clients. Additionally, HSJ1
prevents client aggregation, shields clients against chain trimming by
ubiquitin hydrolase, and stimulates their sorting to the proteasome. In this way,
HSJ1 isoforms participate in endoplasmic reticulum-associated degradation
(ERAD) and protect neurons against cytotoxic protein aggregation.
Overexpression of Hsp70, Hsp40, HSJ1a and HSJ1b significantly reduce protein
inclusion formation in a model of X-linked spinal and bulbar muscular atrophy
(SBMA) [45]. HSJ1a can also mediate a significant decrease in the number of
inclusions formed in a primary neuronal model of protein aggregation. Studies
on the mechanism underlying the reduction of these inclusions suggest that
Hsp70 and Hsp40 increase chaperone-mediated refolding [46]. In contrast,
expression of HSJ1 does not promote chaperone activity but cause an increase
in ubiquitination. These findings clearly demonstrate that HSJ1 proteins
mediate an increase in targeting protein degradation via the UPS.
Perspectives
The strong links between protein misfolding/aggregation and
neurodegenerative diseases require a better understanding of the factors and mechanisms
involved in protein quality control systems (Fig. 2). The chaperones
promote folding/refolding of the misfolded proteins (such as Ab, a-Syn and
polyQ-expanded proteins) and reduce the aggregates formed by misfolded
proteins, while the UPS components assist degradation of the misfolded proteins
and eliminate the aggregates. Cooperation of chaperone machineries and UPS is
accomplished by some special cofactors (such as CHIP, BAG1 and HSJ1). It is
apparent that the molecular chaperones and the UPS components work
coordinately to keep the cell in a stable and well-operated state. Identifying
new factors linking chaperone bound substrates to proteasome degradation will
help us understand more about the mechanism of molecular cooperation. Advances
in the research of protein folding/misfolding and degradation in eukaryotic
cells will shed light on the feasibility of clinical application of chaperones
and UPS components in neurodegenerative diseases.
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