Traffic 2012; 13: 771–779
2012 John Wiley & Sons A/S
doi:10.1111/j.1600-0854.2012.01347.x
Review
HDAC6 at the Intersection of Neuroprotection and
Neurodegeneration
Constantin d’Ydewalle1,2 , Elke Bogaert1,2 and
Ludo Van Den Bosch1,2∗
1 Vesalius
Research Center, VIB, Campus Gasthuisberg,
Leuven, Belgium
2 Laboratory of Neurobiology, KU Leuven, Leuven,
Belgium
*Corresponding author: Ludo Van Den Bosch,
ludo.vandenbosch@vib-kuleuven.be
Histone deacetylase 6 (HDAC6) catalyzes multiple reactions. We summarize the current knowledge on HDAC6,
its targets and functions. Among others, HDAC6 recognizes damaged proteins and assures that these proteins
are destroyed by autophagy. On the other hand, HDAC6
also modifies the tracks used by the clearance mechanism so that axonal transport becomes less efficient.
We hypothesize that a disturbance in the equilibrium
between the different functions of HDAC6 could play an
important role in neurodegeneration.
Key words: autophagy, axonal transport, deacetylation,
HDAC6, microtubules, neurodegeneration, post-translational modifications
Received 27 September 2011, revised and accepted for
publication 23 February 2012, uncorrected manuscript
published online 28 February 2012, published online 26
March 2012
Histone deacetylase (HDAC) enzymes are intriguing
targets involved in a broad range of biological processes,
including genetic, epigenetic and oncogenic processes
(1–4). HDACs ensure the reversible acetylation of histones
and play a crucial role in transcriptional regulation and
histone metabolism (1,5). Given their importance in these
processes, a wide range of medicinal chemistry studies
aimed to develop HDAC inhibitors to treat tumors and
other malignancies (2,4).
Recently, the attention of scientists working in the field
of neurodegeneration has been drawn to HDACs, and
in particular to HDAC6, as it could be a key player in
many neurodegenerative disorders. In this review, we will
summarize the current knowledge on HDAC6, its targets
and functions in autophagy and axonal transport, and we
propose a new model in which HDAC6 orchestrates its
activities in neurodegenerative diseases.
HDAC6 and the HDAC Family
The HDAC family consists of 18 members classified
into two groups: zinc-dependent enzymes (HDAC1–11)
and nicotinamide adenine dinucleotide (NAD+ )-dependent
enzymes (sirtuin 1–7) (Figure 1). On the basis of sequence
homology of the catalytic domain to yeast, HDACs have
been further classified into different classes. Class I
HDACs (HDAC1, 2, 3 and 8) are homologous to the
yeast Rpd3 protein (Figure 1). They are ubiquitously
expressed and are generally detected in the nucleus.
Class II comprises HDAC4, 5, 7 and 9 (class IIa) as well as
HDAC6 and 10 (class IIb) (Figure 1). Class II HDACs share
sequence homology with the yeast Hda1 protein and
shuttle between the nucleus and the cytoplasm. HDAC11
is the only member of class IV HDACs (Figure 1). It
shows similarity to the catalytic domains of both class
I and II enzymes. Class III HDACs comprise the NAD+ dependent sirtuins that are homologous to the yeast Sir2
protein (Figure 1).
The amino acid sequence outside the catalytic domain
is highly variable suggesting that these enzymes might
exert their deacetylating function on other substrates than
histones. Moreover, HDAC6 is unique as it is the only
HDAC that contains two functional N-terminally located
catalytic sites in combination with an ubiquitin-binding
domain at the C-terminal part of the protein (Figure 1)
(6). HDAC10 contains a second leucine-rich region that is
thought to represent a catalytically inactive deacetylase
domain (7). HDAC6 is also the only HDAC with an
exclusive cytoplasmic localization, suggesting that its
activity is histone-independent and does not influence
transcriptional processes (6).
Target Proteins for HDAC6-Mediated
Deacetylation
A major breakthrough in the search of molecular
targets was the discovery of acetylated tubulin in
polymerized microtubules as a substrate for HDAC6
(6,8,9). Pharmacological inhibition or downregulation of
HDAC6 in cellular and animal models increases acetylated
tubulin abundance (6,8–13).
Several proteins acting through different cellular pathways
regulate HDAC6-mediated deacetylation of microtubules.
The Akt-dependent glycogen synthase kinase-3β (GSK-3β)
increases the deacetylase activity of HDAC6 on tubulin as
shown in hippocampal neurons (Figure 2)(12). Although
GSK-3β and HDAC6 do colocalize, a direct interaction
between these two proteins has not been demonstrated
(12). Alternatively, the tubulin polymerization-promoting
protein (TPPP/p25) is an unstructured protein that aligns
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Figure 1: Classification of HDAC enzymes. Zinc (Zn)-dependent or NAD+ -dependent HDACs are shown to scale and are categorized
into classes (I–IV) according to their homology to yeast. Class I HDACs (1, 2, 3 and 8) show homology to Rpd3. Class II HDACs, including
4, 5, 7 and 9 (class IIa) as well as 6 and 10 (class IIb), are homologs of yeast Hda1. Class III HDACs comprise SIRT1–7 and show
homology to yeast Sir2. Class IV HDACs (HDAC11) show homology to both class I and II HDACs. HDAC6 is the only HDAC with two
N-terminal active deacetylating domains and a C-terminal ubiquitin-binding domain.
along the microtubule network and affects microtubule
dynamics and cell motility (14). Binding of TPPP/p25
to HDAC6 directly inhibits the deacetylating function
of HDAC6 in HeLa cells (Figure 2) (14). Finally,
the microtubule-associated protein Tau, which ensures
stabilization of the microtubular network, also binds to
HDAC6 and decreases the deacetylase activity of HDAC6
in neuronal cell lines (Figure 2) (15,16). In line with these
findings, Tau knockout mice demonstrate decreased
acetylated tubulin levels as the inhibitory effect of Tau
on HDAC6 is abolished (16). Recently, it has been found
that Tau is deacetylated mainly by sirtuin-1, a class III
HDAC, and to a lesser extent by sirtuin-2 and HDAC6
(17). Thus, HDAC6 plays a regulatory role in the stability
of microtubule dynamics, thereby influencing neuronal
extension and polarization of neurons (8,11).
Acetylation is required for the recruitment and anchoring
of molecular motor proteins coupled to their cargo and
to microtubules (18). It has been proposed that HDAC6
might regulate axonal transport either directly by binding
to motor proteins or indirectly by altering the acetylation
state of microtubules. HDAC6 indeed interacts with core
components of the dynactin complex such as p150(glued)
and actin-related protein-1 (Arp1) in non-neuronal cell lines
(Figure 2) (6,9). Moreover, inhibition or knockdown of
HDAC6 in cultured neurons increases the axonal transport
of mitochondria by increasing acetylated tubulin amounts
and the concomitant recruitment of motor protein dynein
and kinesin-1 to microtubules (10,12).
Microtubules are in a dynamic equilibrium consisting of
stages of depolymerization, repolymerization and stable
microtubules. Microtubules containing high levels of
acetylated tubulin are more resistant to drug-induced
depolymerization indicating that tubulin acetylation is
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a marker for stable microtubules in fibroblasts (8).
Overexpression of HDAC6 induces depolymerization and
subsequent deacetylation, indicating that tubulin dimers
and monomers are deacetylated, while acetylation only
occurs in polymerized microtubules (8). In cultured
neurons, HDAC6 is enriched at the distal ends of axons
where it interacts with end-binding protein-1 (EB-1) and
Arp1, both accumulating at growing tips of microtubules
(Figure 2) (9). Moreover, inhibition or downregulation of
HDAC6 results in reduced axonal length and decreased
growth and shrinkage velocity of microtubules (9,11).
As HDAC6 affects microtubule dynamics, it has been
suggested that this enzyme also regulates cell motility.
However, global HDAC6-mediated deacetylation of tubulin
in mouse embryonic fibroblasts is not sufficient to induce
changes in cell motility (19). Upon stimulation with growth
factors, HDAC6 translocates to actin-enriched membrane
ruffles where it binds and deacetylates cortactin (Figure 2)
(19,20). The latter protein is a cortical actin-binding protein
and promotes the polymerization and rearrangement of
the actin cytoskeleton, especially the actin cortex around
the cellular periphery. Deacetylation of cortactin changes
its binding capacity to F-actin, eventually altering actin
polymerization (20).
More recently, redox regulatory proteins peroxiredoxin I
(PRX1) and II (PRX2) were identified as specific targets
of HDAC6 in non-neuronal cell lines (21). PRX1 and PRX2
are antioxidant enzymes that reduce H2 O2 levels (Figure
2). Acetylation of PRX increases their reducing activity,
their resistance to superoxidation and to transition to
high-molecular mass complexes. Inhibition of HDAC6
deacetylase activity with a consequent accumulation of
acetylated PRX could lead to a beneficial increase in
antioxidant activity (21).
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Figure 2: HDAC6 and its substrates for deacetylation. HDAC6 interacts with a wide variety of targets. HDAC6 binds to and
deacetylates polymerized microtubules. It also interacts with EB-1, p150(glued) and Arp1 of the dynactin motor complex, affecting
microtubule dynamics and cell motility. While the Akt-dependent GSK-3β increases HDAC6-mediated tubulin deacetylation, both Tau and
TPPP/p25 inhibit this reaction. HDAC6 also interacts with and deacetylates cortactin, changing its binding affinity to filamentous actin
and ultimately changing actin polymerization. HDAC6 deacetylates PRX1 and PRX2 altering their reducing capacity of water peroxide
(H2 O2 ) to hydrogen (H2 O). Finally, HSP90 is deacetylated by HDAC6 affecting the downstream targets of HSP90.
Finally, the molecular ATP-dependent chaperone heatshock protein 90 (HSP90) is also a substrate of HDAC6
(Figure 2) (22). The reversible acetylation of HSP90
regulates its chaperone activity (22–24). As a chaperone
protein, HSP90 is a critical player in a wide variety of
cellular signaling pathways as it facilitates the structural
maturation and assembly of its client proteins. HSP90
binds to multiple client proteins, including heat-shock
factor 1 (HSF1) under basal conditions. In HDAC6-deficient
regulatory T cells, HSF1-regulated genes including HSP90
were upregulated (25,26). The proteins encoded by these
genes showed an increased acetylation state compared to
wild-type cells (25,26). Furthermore, as we will discuss in
detail in the next chapter, HDAC6 senses the presence of
ubiquitinated aggregates and consequently induces the
expression of major cellular chaperones by triggering
the dissociation of a repressive HDAC6/HSF1/HSP90
complex and subsequent HSF1 activation (27). Inhibition
of HDAC6 also induces a reduction in binding of HSP90
to vascular endothelial growth factor receptor 1 and 2
(VEGFR1/Flt1 and VEGFR2/Flk1, respectively), followed
by increased binding of HSP70 to these receptors (28).
Knockdown of HDAC6 leads to a depletion of VEGFR1/Flt1
and VEGFR2/Flk1 (28). These results indicate that
HDAC6 plays an important role in the HSP90-mediated
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regulation of VEGFRs, and possibly other targets of
HSP90 (28).
Interestingly, vascular endothelial growth factor (VEGF)
has protective effects in motor neuron disease, as
shown both in vitro and in vivo (29–32). The direct
or indirect effects of HDAC6-mediated deacetylation
on molecular chaperones that are associated with
VEGF (and its receptors) and neurodegeneration suggest
that HDAC6 might play a role in neurodegenerative
diseases. Exciting information has been obtained in
transgenic mice with targeted disruption of HDAC6.
Young HDAC6 knockout mice do not show any overt
phenotype (33). Genetic ablation of HDAC6 leads to
hyperacetylation of microtubules and HSP90 without
any obvious abnormal effects on development and
survival of these mice (33). Another strain of HDAC6
knockout mice demonstrate ubiquitin-positive aggregates
and apoptotic cell death, both pathogenic hallmarks of
neurodegeneration, in the brain from 6 months of age
on (34). Similarly, a neurodegenerative phenotype was
observed in Drosophila with selective HDAC6 deficiency
in photoreceptor neurons (34). Together, these in vivo
data indicate that HDAC6 plays a crucial protective role in
neurodegeneration.
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Figure 3: The role of HDAC6 in autophagy. A finely tuned balance between VCP/p97 and HDAC6 directs ubiquitinated aggregates
either to the UPS or to the autophagic pathway. HDAC6 binds to ubiquitinated aggregates via its ubiquitin-binding domain as well
as to dynein motor proteins. A dynein-mediated retrograde transport leads to accumulation of aggregates into an aggresome at the
perinuclear region. HDAC6 also contributes to autophagosome formation by interacting with ATGs. HDAC6 also participates in the fusion
of autophagosomes and lysosomes to autophagolysosomes, the final step prior to lysosomal degradation of ubiquitinated aggregates.
FUS/TLS and TDP-43 bind to HDAC6 mRNA in stress granules.
Role of HDAC6 in Autophagy
Cells deal with protein aggregates in multiple ways. In
several of these processes, HDAC6 has been shown to
play a crucial role. Autophagocytosis is a catabolic process
in which degradation of damaged organelles and/or
ubiquitinated proteins and aggregates occurs through
the lysosomal pathway. Microautophagy is a process
in which the lysosomes directly engulf cytoplasm by
invagination, protrusion or septation of the lysosomallimiting membrane. Macroautophagy, also referred to
as autophagy, on the other hand, sequesters damaged
organelles and ubiquitinated aggregates in a doublemembrane vesicle called autophagosomes that fuse with
lysosomes. Neuronal survival is dependent on autophagy
due to its postmitotic nature, the polarized morphology
and active protein trafficking (35). The majority of studies
suggest that autophagy is a compensatory mechanism
that is activated when the ubiquitin proteasome system
(UPS) is impaired (36,37). It is still unclear, however,
whether autophagy and the UPS are independent
processes (38). Nevertheless, as HDAC6 contains an
ubiquitin-binding domain, it was suggested that it also
plays a role in protein quality control (34,37,39).
As stated above, HDAC6 inhibition triggers the
dissociation of a repressive HDAC6/HSP90/HSF1 complex
and leads to HSF1 activation and induces the expression of
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HSF1-responsive genes including molecular chaperones
(Figure 3) (27). These chaperones are intrinsically associated with ubiquitinated misfolded proteins that are prone
to aggregation. Nevertheless, HDAC6 is not required
for autophagy activation per se. It is rather recruited
to poly-ubiquitinated autophagic substrates (27,34,39).
A finely tuned balance between valosin-containing protein (VCP)/p97 and HDAC6 directs the fate of ubiquitinated aggregates (Figure 3). VCP/p97 promotes ubiquitin
chain turnover and protein degradation through the UPS,
whereas HDAC6 favors the accumulation of ubiquitinated proteins and subsequent perinuclear aggregation
(27,40,41). This hypothesis is strengthened by the observation that VCP/p97 and HDAC6 interact with each other
(Figure 3) (41). However, the functional consequences of
this interaction are not yet clear.
Aggregation can occur both in the cell body and in
extended processes of neurons, while the aggresome
(i.e. accumulated aggregates) is formed at the perinuclear
region. This implies that ubiquitinated aggregates are
transported retrogradely toward this region. An elegant
study demonstrated that HDAC6 associates with the
dynein motor protein complex and recruits ubiquitinated
protein aggregates to dynein (Figure 3) (39).
Next, autophagic vacuoles are formed that encapsulate
the ubiquitinated aggregates. The formation of these
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autophagosomes depends on autophagy-related (Atg) proteins that are molecular determinants during nucleation,
elongation and maturation of these vacuoles. Pharmacological inhibition and ablation of HDAC6 interferes with
the recruitment of Atg-8/LC3 to the aggresome (Figure 3)
(37). HDAC6 also stimulates autophagosome–lysosome
fusion by promoting F-actin remodeling in a cortactindependent manner (Figure 3) (34). Lysosomal recruitment
also requires an intact microtubule structure as druginduced depolymerization of microtubules disrupts perinuclear accumulation of lysosomes (Figure 3) (37,42).
Conversely, HDAC6 deficiency leads to failure of
autophagosome maturation, protein aggregate build-up
and neurodegeneration (34).
Another essential part of the cellular response to protein
aggregation is the reversible translational suppression.
This process occurs in cytoplasmic stress granules (SGs)
that are dense globules containing stress proteins and
untranslated mRNAs. SGs are formed in a microtubuledependent manner during cellular stress and are protective in nature (42). Like autophagy, SGs are formed when
the UPS is impaired, suggesting that both autophagy
and translational suppression occur simultaneously (43).
HDAC6 appears to colocalize and interact with Ras-GAP
SH3 domain-binding protein (G3BP), an SG marker, indicating that HDAC6 might contribute to SG formation (Figure
3) (42).
The contribution of HDAC6 to SG formation depends
on its two hdac domains (42). Pharmacological inhibition
or genetic disruption of HDAC6 indeed abolishes SG
formation (42). The deacetylating function of HDAC6 is
thus critically important for SG formation. Whether G3BP
or other SG markers are activated directly or indirectly
by HDAC6-mediated deacetylation is not known. Blocking
the dynein motor proteins does not affect the localization
of HDAC6, while it does impair SG formation (42).
Like in the autophagic pathway, an intact and densely
acetylated microtubular network seems to contribute to
SG formation, possibly by enhancing trafficking of SG
components (42).
TAR DNA-binding protein-43 (TDP-43) and fused in
sarcoma/translocated in liposarcoma (FUS/TLS) are RNAbinding proteins that are found in SGs. TDP-43 and
FUS/TLS form a functional complex that binds to HDAC6
mRNA (Figure 3). Silencing either TDP-43 or FUS/TLS
reduces HDAC6 mRNA levels, indicating a crucial link
between these RNA-binding proteins and HDAC6 (44).
Competition experiments indicated that TDP-43 and
FUS/TLS occupy overlapping binding sites on HDAC6
mRNA (44). A Drosophila model in which TDP-43 is
silenced confirmed the decreased HDAC6 expression.
In cells in which TDP-43 is silenced, cellular aggregate
formation and increased cytotoxicity are found (45).
Finally, HDAC6 overexpression is able to rescue the phenotype of a Drosophila model of spinobulbar muscular
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atrophy, indicating that HDAC6 might partially counteract
the pathogenesis of neurodegenerative disorders characterized by an impaired UPS (36). All together, these data
strongly suggest that HDAC6 is a master regulator of
the protective response to cytotoxic protein aggregation
through autophagy and SG formation.
HDAC6 is a Key Enzyme in
Neurodegenerative Diseases
Recently, it has become clear that microtubule acetylation
and microtubule dynamics play a crucial role in flagellar
transport of cilia. Moreover, HDAC6 has been shown
to be an important tubulin deacetylase, in particular of
axonemal microtubules. HDAC6 thus might be a promising
therapeutic target for ciliopathies that give rise to a wide
variety of symptoms such as multiorgan failure with
variable central nervous system involvement (46–48).
Ubiquitinated aggregates are a common feature of many
neurodegenerative disorders. Given its role in autophagic
degradation of ubiquitinated aggregates, HDAC6 has been
associated with a wide variety of neurodegenerative
diseases.
Alzheimer’s disease is the most common form of
dementia and is characterized by amyloid plaques and
neurofibrillary Tau tangles in and around cortical neurons.
In patients with Alzheimer’s disease, contradicting
information has been obtained. Although HDAC6 appears
to be upregulated, acetylated tubulin levels are increased
in neurons containing neurofibrillary Tau pathology (15,16).
Inhibition of the proteasome system in cellular models
potentiates the interaction between HDAC6 and Tau, and
facilitates perinuclear aggregation of Tau independently of
the deacetylase activity (15).
The characteristic hallmarks of Parkinson’s disease (PD)
include movement-related symptoms (such as shaking,
rigidity and slowness of movement) and difficulty with
walking caused by selective neuronal death in the
substantia nigra. Cellular models demonstrated that
HDAC6 expression increases and colocalizes with mutant
α-synuclein, one of the genetic causes of familial PD, in
the perinuclear region forming aggresome-like structures
(49). HDAC6 deficiency blocks the formation of aggregates
and interferes with autophagy (49). Immunohistochemical
and ultrastructural analysis of post mortem tissue from
patients with PD and dementia with Lewy bodies (DLBs)
demonstrated strong HDAC6 positivity on the filamentous
structures within Lewy bodies (39,50). Parkin, associated
with early-onset PD, promotes mitophagy by catalyzing
mitochondrial ubiquitination (51). This recruits ubiquitinbinding autophagic components HDAC6 and p62, leading
to mitochondrial clearance (51). In a Drosophila model
for PD, depletion of HDAC6 significantly increases the
loss of dopaminergic neurons, retinal degeneration and
locomotor dysfunction (52). Conversely, overexpression
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d’Ydewalle et al.
of HDAC6 promotes inclusion formation and suppresses
the α-synuclein-induced loss of neurons and retinal
degeneration (52).
Huntington’s disease (HD) is caused by an increase
in CAG repeats (>28 repeats) in the Huntingtin (HTT )
gene [poly(Q) in Htt] and leads to defects in muscle coordination (‘chorea’), cognitive decline and dementia. In
HD brains, acetylated tubulin levels are decreased (10). In
vitro models of HD demonstrated that HDAC6 inhibition
restores acetylated tubulin abundance and subsequently
the axonal transport defects observed in diseased states
(10). However, genetic disruption of HDAC6 in HD
mice indicated that the aggregate load as well as the
axonal transport defects are not restored, while tubulin
acetylation is increased (53). HDAC6 deficiency in HD
mice also does not influence the disease progression at
the behavioral level (53).
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by the selective loss of motor neurons
in the spinal cord, brainstem and motor cortex. The symptoms include spasticity and rapidly progressive weakness
and muscle atrophy followed by death due to respiratory failure. Ubiquitinated aggregates have been observed
in several models as well as in patients, indicating that
HDAC6 might be involved. This notion is supported by
the association of mutations in TDP-43 and FUS/TLS
as a cause of familial ALS, which form a complex and
bind to HDAC6 mRNA in SGs. In addition, mutations in
VCP/p97 have been associated with ALS (54). Mutant
VCP mice demonstrate progressive muscle weakness,
TDP-43 pathology in muscle and brain. Although it has
been suggested that an impaired nuclear factor-κB (NFκB) pathway or decreased ATP levels might underlie the
phenotype in mouse and Drosophila models, respectively,
the close links between VCP, TDP-43 and HDAC6 suggest
that HDAC6 might contribute to disease pathogenesis (54–56). Recently, mutations in the gene encoding
ubiquilin-2 (UBQLN-2 ) have been associated with hereditary ALS (57). Ubiquilin-2 physically associates with both
the proteasome and ubiquitin ligases and thus functionally
links the ubiquitination machinery to the UPS. These findings further indicate that the autophagic pathway might
be compromised in the underlying disease mechanism of
ALS (57). Treatment with an HDAC inhibitor also delays
disease progression and increases survival in a mouse
model of ALS, further supporting the notion that HDAC6 is
a central enzyme in the disease (58). Moreover, rapid muscle denervation due to axonal loss and defects in axonal
transport is observed in cellular and animal models of ALS
in which HDAC6 also might play a role (18,59). All together,
these observations point toward a potential role of HDAC6
in ALS pathology. However, a cross-breeding experiment
with HDAC6−/− mice and mouse models of ALS will help
to elucidate the exact role of HDAC6 in ALS pathology.
Charcot-Marie-Tooth (CMT) disease is the most common
inherited disorder of the peripheral nervous system.
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Clinical symptoms include progressive weakness and
atrophy of distal limb muscles, sensory defects, skeletal
deformities and steppage gait. Approximately 40 causative
genes have been associated with CMT. Although
biochemical studies are sparse, some of the mutant
proteins have been shown to form aggregates in
cellular models of CMT (60–65). Moreover, mouse
models recapitulating mutant small heat-shock protein B1
(HSPB1)-induced CMT demonstrate reduced acetylated
tubulin levels in peripheral nerves, leading to severe
axonal transport defects (13,62). Although the exact
link between mutant HSPB1 and HDAC6 remains
elusive, pharmacological inhibition of HDAC6 rescues the
phenotype of mutant HSPB1 mice and restores the axonal
transport defects (13).
Increased expression of HDAC6 is observed after injury
to neurons (66). Pharmacological and genetic approaches
demonstrate that HDAC6 inhibition promotes survival and
regeneration of neurons, indicating that HDAC6 is a target
for both regeneration and protection in neurodegenerative
diseases (66).
Hypothesis: HDAC6 Combines Protective and
Degenerative Functions
To reconcile both protective and degenerative functions
of HDAC6, we propose a two-hit model in which both
functions of HDAC6 lead to disease. The combined
presence of deacetylating domains and an ubiquitinbinding motif within the same enzyme implies that there
is a structural and functional link between both functions.
In many neurodegenerative disorders, toxic ubiquitinated
aggregates accumulate during the disease process
(Figure 4). HDAC6-mediated HSF1 activation increases
stress-response protein levels in order to target misfolded
proteins to the UPS, which represents the first line of
defense of the neuron (Figure 4). This process eventually
saturates and/or the UPS becomes impaired. When this
occurs, HDAC6 drives the ubiquitinated aggregates to
the autophagy pathway by shifting the balance from the
UPS to autophagy through its interaction with VCP/p97
(Figure 4) (27,36,37). HDAC6 also recruits the aggregates
through dynein motors that transport them to the
perinuclear region for aggresome formation (Figure 4) (39).
Simultaneously, HDAC6 contributes to SG formation in
order to preserve untranslated mRNAs (Figure 4) (42,43).
In general, HDAC6-mediated deacetylation of its substrates is considered to have a beneficial effect on
neuronal functioning as described above. Under basal
conditions, HDAC6 might have only moderate deacetylating capacity. It has been suggested that an excess of
HDAC6 favors the accumulation of ubiquitinated aggregates (67). The accumulation of HDAC6 thus could lead
to increased tubulin and cortactin deacetylation eventually
causing a disturbance of microtubular and actin dynamics,
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Histone Deacetylase 6 in Neurodegeneration
Figure 4: Proposed roles of HDAC6 in neuroprotection and neurodegeneration. Over time, aggregate-prone proteins form insoluble
ubiquitin-positive aggregates that lead to impairment of the UPS. VCP/p97 shifts the equilibrium from the UPS to the autophagic pathway.
HDAC6 is recruited to ubiquitinated aggregates. Once recruited, HDAC6 plays both neuroprotective and neurotoxic functions. HDAC6
is involved in stress granule formation in which translation is silenced in stressed cells. Dynein motor proteins interact with HDAC6
bound to ubiquitinated aggregates. This complex is then transported to the perinuclear region where the aggresome is formed. HDAC6
recruitment to aggregates also leads to a local accumulation of HDAC6 causing hyperdeacetylation of its substrates. Deacetylation
of HSP90 and peroxiredoxins causes toxic insults, while deacetylation of tubulin and cortactin leads to cytoskeletal alterations. The
accumulation of toxic insults and changes in microtubule and actin dynamics eventually lead to neurodegeneration.
respectively (Figure 4). Both are crucial cytoskeletal structures for neurons and their axons. Moreover, deacetylation of tubulin potentially compromises axonal transport,
as recruitment and anchoring of motor proteins are
reduced (10,13). Increased HDAC6-mediated deacetylation of PRXs and HSP90, combined with the perinuclear
load of aggresomes, could lead to higher incidence of toxic
insults (including increased presence of aggregate-prone
proteins and reactive oxygen species) eventually inducing
neurodegenerative diseases (Figure 4).
In conclusion, our model illustrates the main neuroprotective function of HDAC6 as a clearance mechanism
for ubiquitinated proteins. At later stages of the disease,
the equilibrium could shift to effects that contribute to
neurodegeneration, including a disturbance of the axonal
transport. An immediate consequence of this hypothesis
is that therapeutic strategies should focus on the negative aspects of HDAC6, leaving the beneficial effects
unaffected.
Acknowledgments
Research of the authors is supported by grants from the Fund for Scientific
Research Flanders (FWO-Vlaanderen), the University of Leuven, the
Belgian government (Interuniversity Attraction Poles, programme P6/43
of the Belgian Federal Science Policy Office), the Association Belge contre
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les Maladies neuro-Musculaires (ABMM), the Association Française contre
les Myopathies (AFM), the Frick Foundation for Amyotrophic Lateral
Sclerosis Research, the Muscular Dystrophy Association, the European
Community’s Health Seventh Framework Programme (FP7/2007-2013
under grant agreement 259867) and the Latran Foundation. C. d. Y.
is supported by the Agency for Innovation by Science and Technology
in Flanders (IWT-Vlaanderen). E. B. is a postdoctoral fellow of FWOVlaanderen.
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