nihms304302.pdf

The role of I

B kinase complex in the neurobiology of

Huntington's disease

Ali Khoshnan

and

Paul H. Patterson

Abstract

The I

B kinase

(IKK

) is a prominent regulator of neuroinflammation, which is implicated in

the pathogenesis of Huntington's disease (HD). Inflammatory mediators accumulate in the serum

and CNS of premanifest and manifest HD patients, and cytokine levels correlate with disease

progression. IKK

may also directly regulate the neurotoxicity of huntingtin (Htt). Activation of

IKK

by DNA damage triggers caspase-dependent cleavage of WT and mutant Htt and enhances

the accumulation of oligomeric fragments. Moreover, the N-terminal fragments of mutant Htt

(HDx1) directly bind to and activate IKK

. Thus, the IKK

-dependent cleavage of full-length

mutant Htt and the buildup of HDx1 could form a deleterious feed-forward loop. Elevated IKK

activity is present throughout the CNS in a symptomatic mouse model of HD expressing HDx1,

whereas in asymptomatic mice with full-length mutant Htt, it is confined to the striatum. IKK

could also influence the phosphorylation of Htt at Ser13 and Ser16, which is linked to HD

pathology. IKK

inhibitors ameliorate the toxicity of mutant Htt in striatal neurons and prevent

DNA damage-induced Htt cleavage. Inhibition of IKK

in the CNS also reduces

neuroinflammation and imparts neuroprotection in a chemical model of HD. These findings

support an active role for IKK

in HD pathogenesis and represent an example of how gene–

environment (exemplified by DNA damage and inflammation) interactions can influence Htt

neurotoxicity. We will summarize these findings and describe the therapeutic potentials of IKK

for HD.

Keywords

Huntington's disease; IKK

; Neuroinflammation; Htt cleavage; DNA damage

Introduction

Huntington's disease and IKK

HD is an inherited neurodegenerative disorder caused by expansion of a CAG repeat,which

is translated into a polyglutamine (polyQ) stretch in exon-1 (HDx1) of Htt. (The

Huntington's Disease Collaborative Research Group (1993). In most animal and cellular

models of HD, the neurotoxicity of mutant Htt is enhanced by the cleavage and production

of N-terminal fragments, which are generated by various enzymes including caspases and

calpains. The fragments containing expanded polyQ aberrantly bind to various proteins,

impair cellular machinery, and promote neurotoxicity. The N-terminal mutant Htt fragments

also form amorphous intracellular aggregates and accumulate in the HD brain. The role of

these aggregates in the pathobiology of HD remains a contentious area of investigation.

Wild type Htt is also cleaved by similar proteases, which can lower its level and interfere

with its vital function in neurons. Therefore, both the loss of WT Htt and the gain of toxic

Corresponding author at: Biology Division, 216-76, California Institute of Technology, Pasadena CA 91125, USA.

Khoshnan@caltech.edu (A. Khoshnan).

NIH Public Access

Author Manuscript

Neurobiol Dis

. Author manuscript; available in PMC 2011 August 1.

Published in final edited form as:

Neurobiol Dis

. 2011 August ; 43(2): 305–311. doi:10.1016/j.nbd.2011.04.015.

NIH-PA Author Manuscript

functions by mutant Htt contribute to HD. Studies on the neurobiology of HD were

extensively reviewed recently (Zuccato and Cattaneo, 2010). Although expansion of polyQ

is a determinant of HD, the age of disease onset is variable among patients with similar

polyQ length (Wexler et al., 2004). Thus, other genetic or environmental factors may

regulate the onset and progression of HD.

Two potential modifiers of HD pathogenesis are neuroinflammation and the accumulation of

DNA damage in the brain. A prominent pathway regulating the effects of these

environmental insults is the I

B kinase (IKK) complex. The core IKK has two kinases,

IKK

and IKK

, and a regulatory subunit, IKK

. IKK is induced by various stimuli

including cytokines, oxidative stress and DNA damage, and it phosphorylates the inhibitors

B (I

B), a family of proteins that sequesters NF-

Bs in the cytoplasm (Hacker and

Karin, 2006). Phosphorylation of I

Bs initiates their degradation by the ubiquitin–

proteasome pathway, which liberates NF-

B and allows its binding to the promoter of many

genes such as cytokines (Fig. 1). IKK

is the predominant kinase responsible for

inflammatory responses (Hacker and Karin, 2006). The IKKs are ubiquitously expressed but

their functions in the CNS are poorly understood. While regulated IKK/NF-

B signaling is

thought to promote neuronal survival, growth and plasticity, chronic activation of IKK

contributes to neurodegeneration (Mattson and Meffert, 2006). Excessive IKK

activity,

which coincides with elevated cytokines, has been detected in Alzheimer's disease (AD),

multiple sclerosis (MS), Parkinson's disease (PD), ischemia, and HD (Khoshnan et al., 2004;

Herrmann et al., 2005; Mattson and Meffert, 2006; Van Loo et al., 2006; Ghosh et al.,

2007). On the other hand, inhibition of IKK

activity is neuroprotective in animal models of

PD, ischemia, and MS (Herrmann et al., 2005; Van Loo et al., 2006; Ghosh et al., 2007).

Recent studies demonstrate that the nuclear orphan receptor Nurr-1, which is mutated in

certain familial cases of PD, is an inhibitor of NF-

B pathway (Saijo et al., 2009).

Moreover, optineurin, a negative regulator of IKK assembly, is mutated in familial cases of

amyotrophic lateral sclerosis (ALS) and is the underlying cause of elevated levels of IKK/

NF-

B in these patients (Zhu et al., 2007; Maruyama et al., 2010). Thus, dysregulation of

IKK/NF-

B may contribute to the pathology of major CNS diseases.

IKK/NF-

B signaling and inflammation in HD

Neuroinflammation, signified by activated microglia and elevated levels of proinflammatory

cytokines, is a component of major neurodegenerative disorders including AD, PD, ALS,

and HD (Björkqvist et al., 2008; Glass et al., 2010). While the role of inflammation in these

disorders is not well characterized, the accumulation of amyloid proteins, which is a

hallmark of these disorders, may be causal. HD patients express increased levels of the

inflammatory cytokine IL-6 in the serum and CNS ~ 16 years before the onset of symptoms,

and its level correlates with disease development. Other cytokines, including IL-1

, IL-8 and

TNF-

are also abundant in the symptomatic HD patients as well as in HD animal models

(Björkqvist et al., 2008). Studies of postmortem HD brains also indicate abnormal level of

several inflammatory mediators, including CCL2, IL-10, IL-6, IL-8 and MMP9 in various

brain regions (Silvestroni et al., 2009). The IKK/NF-

B pathway is major inducer of these

inflammatory mediators and is dysregulated in HD (Khoshnan et al., 2004; Hacker and

Karin, 2006). Elevated IKK

activity is widespread in the CNS of R6/2 a genetic mouse

model of HD, which expresses a toxic N-terminal fragment of mutant Htt (HDx1)

(Khoshnan et al., 2004; Zuccato and Cattaneo, 2010). These animals also express high levels

of inflammatory cytokines including IL-6, IL-1

and TNF-

in the serum and CNS, which is

consistent with a deregulated IKK

/NF-

B pathway (Björkqvist et al., 2008). Activated

microglia, which are a likely source of elevated cytokines in the CNS, are detected in

preclinical HD brains and their accumulation coincides with striatal neuronal dysfunction

(Tai et al., 2007). Interestingly, inhibition of caspase-mediated maturation of IL-1

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ameliorates neuroinflammation and neurotoxicity in a R6/2 mouse model (Ona et al., 1999).

Moreover, knockdown of IKK

in microglia reduces inflammation and neurotoxicity in a

kainic acid-induced excitotoxicity model of HD (Cho et al., 2008). These studies support a

role for IKK

in neuroinflammation and highlights that imbalances in IKK

activity may be

the underlying cause of elevated cytokines in the CNS of HD patients. Aberrant activity of

IKK

/NF-

B may also be responsible for the abnormal level of inflammatory mediators in

the serum of HD patients. Immune cells of HD patients are hypersensitive to immunological

challenges and produce various cytokines to significantly higher levels than those from

control subjects (Björkqvist et al., 2008). Moreover, striatal neurons expressing full-length

mutant Htt display exaggerated IKK

/NF-

B activity when stimulated with cytokines

known to activate IKK

(Khoshnan et al., 2004). Thus, mutant Htt may increase the cellular

responses to stimuli that activate IKK

. Considering the prominent role of IKK

in cytokine

biology, it will be interesting to investigate how deregulation of IKK

promotes

inflammation in HD patients many years before the onset of motor symptoms.

Mutant HDx1 activates IKK

One factor, which may activate the IKK/NF-

B, is the accumulation of amyloidogenic

peptides such as the A

fragment of the amyloid precursor protein (Kaltschmidt et al.,

2005). We have shown that mutant HDx1, which has amyloidogenic properties, directly

associates with the IKK

subunit of the IKK complex. The binding of mutant HDx1 to IKK

requires expanded polyQ as well as the proline motifs in HDx1. This interaction promotes

the assembly and activation of the IKK complex and is disrupted by recombinant intrabodies

targeting the polyproline motifs of HDx1 (Khoshnan et al., 2002, 2004). Trimerization of

IKK

is a prerequisite for IKK activation (Agou et al., 2002). We find that soluble mutant

HDx1 promotes the assembly of an SDS-resistant IKK

trimer in a human neuronal model

(Fig. 2, Khoshnan et al., 2009). Binding of HDx1 to IKK

may act as a nucleation signal to

recruit other IKK subunits to form an active complex. Thus, the ability of mutant HDx1 to

directly activate the IKK complex may be the underlying cause of widespread IKK

activity

and neuroinflammation observed in the CNS of R6/2 HD mice (Ona et al., 1999; Khoshnan

et al., 2004; Björkqvist et al., 2008). On the other hand, in a presymptomatic knock-in

mouse model of HD (HdhQ150), which expresses full-length mutant Htt, elevated IKK

activity is only detected in the striatum, a primary target of mutant Htt toxicity. Full-length

mutant Htt is incapable of activating the IKK

, however HDx1 accumulates gradually in the

brain of HdhQ150 (Khoshnan et al., 2004; Landles et al., 2010). Selective sensitivity of the

striatum to environmental insults may trigger the generation of HDx1 and activate IKK

locally in HdhQ150. HDx1 also accumulates in various parts of HD brains and potentially

other tissues (Kim et al., 2001), which may aberrantly activate IKK

. While acute and

regulated activation of IKK

may be protective and essential for physiological homeostasis,

chronic stimulation by the gradual build up of HDx1 could lead to abnormalities such as

neuroinflammation and potentially neurodegeneration in HD.

IKKs regulate the cleavage of Htt

The cleavage of Htt by proteolytic enzymes is a pivotal step in the pathogenesis of HD. N-

terminal fragments with the expanded polyQ repeat are more toxic than full-length mutant

Htt in cellular and animal models of HD and cleavage of full-length mutant Htt is a

prerequisite for the onset of symptoms in certain models. For example, inactivation of the

caspase-6 cleavage site of mutant Htt abrogates neuropathology in YAC-128 HD mice

(Graham et al., 2006). However, other caspases and calpains are also known to cleave Htt

and potentially produce neurotoxic N-terminal fragments (Zuccato and Cattaneo, 2010).

Factors that induce the cleavage of Htt are not well characterized, however both genetic and

environmental modifiers are expected to play a role. One potential environmental factor,

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which may influence HD progression, is the gradual accumulation of DNA damage in aging

brain (Katyal and McKinnon, 2008). Indeed, HD patients contain abnormal levels of DNA

damage in the brain and reduction of WT Htt levels as occurs in HD patients, lowers

neuronal resiliency to DNA damaging agents (Butterworth et al., 1998; Bae et al., 2005;

Anne et al., 2007). In search of factors that could trigger the cleavage of Htt, we discovered

that exposure of human neurons to DNA damaging agents promotes caspase-dependent

cleavage of both WT and mutant Htt (Khoshnan et al., 2009). Interestingly, Htt cleavage

induced by DNA damage is IKK

-dependent. Knockdown of IKK

expression with

shRNAs or blocking its activity with small molecule inhibitors reduces caspase activation

and subsequent Htt cleavage (Khoshnan et al., 2009). IKK

phosphorylates Bcl-xL, which

promotes its degradation in neurons exposed to DNA damaging agents. The reduction of

Bcl-xL triggers caspases that can cleave Htt (Fig. 3). WT Htt is also cleaved in cells exposed

to inflammatory cytokines (Zhang et al., 2006; Thompson et al., 2009). In neurons, WT Htt

regulates many important functions including cell survival, BDNF expression, neurogenesis

and protection from genotoxic stress (Godin et al., 2010; Zuccato and Cattaneo, 2010).

IKK

may therefore contribute to neurodegeneration by lowering and inactivating WT Htt.

At the same time, IKK

-dependent cleavage of mutant Htt can produce substrates for further

processing that generates neurotoxic oligomeric species (Ratovitski et al., 2009). Thus,

IKK

may trigger some of the earliest events in HD pathology in mouse models.

Knockdown of IKK

expression also reduces the toxic effects of DNA damage and

enhances neuronal survival. IKK

is a key regulator of the DNA-damage response and a

determinant of cell survival (Wu et al., 2006; Wu and Miyamoto, 2008). In ischemia and

genotoxic stress, the IKK/NF-

B activation promotes the expression apoptotic genes such as

Noxa and Bim (Inta et al., 2006; Wu and Miyamoto, 2008). DNA damage also promotes the

production of the inflammatory cytokine IL-6, which is likely to be IKK

-dependent and is

elevated early in presymptomatic HD (Björkqvist et al., 2008; Rodier et al., 2009). While

proliferating cells are equipped to repair DNA damage, post-mitotic neurons undergo cell

cycle activation and apoptosis when exposed to DNA damaging agents (Kruman et al.,

2004; Kim and Tsai, 2009). It is intriguing that knockdown expression of IKK

in post-

mitotic human neurons prevents DNA damage-induced incorporation of BrdU, a marker of

DNA synthesis (Fig. 4). Reduction of IKK

also inhibits the activation of pro-apoptotic

caspases (Khoshnan et al., 2009). Thus, IKK

represents an interesting target to prevent

neuronal loss by DNA damage as it may occur with aging brain.

While IKK

promotes Htt cleavage, IKK

has the opposite effect. DNA damage lowers the

activity of IKK

in human neurons and elevating IKK

prevents DNA damage-induced

caspase activation and Htt cleavage (Khoshnan et al., 2009). IKK

is known to inhibit the

activity of IKK

in various models (Chariot, 2009). For example, knockdown of IKK

enhances the IKK

-dependent expression of proinflammatory cytokines in immune cells (Li

et al., 2005). Thus, we predict that the protective effect of IKK

on Htt cleavage may

involve inhibition of IKK

. However, IKK

also influences other signaling pathways that

are neuroprotective. IKK

phosphorylates and promotes the activity of CREB binding

protein (CBP) and histone-3 (Anest et al., 2003; Huang et al., 2007). The ability of IKK

modify histone-3 and CBP activity is important in memory reconsolidation and thus

synaptogenesis in the hippocampus (Lubin and Sweatt, 2007). CBP regulates the expression

of important neuronal genes including BDNF, which is induced by IKK

(Greer and

Greenberg, 2008; Khoshnan and Patterson, in preparation). Considering that both CBP

activity and BDNF expression are reduced in HD brains (Zuccato and Cattaneo, 2010),

factors that enhance IKK

activity may have neuroprotective properties. This is contrary to

the effects IKK

on Htt cleavage and promotion of inflammation in the CNS. Thus, changes

in the homeostasis of the IKKs may be critical determinants of Htt cleavage,

neuroinflammation, and neuronal survival in paradigms such as DNA damage.

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The role of IKK in Htt phosphorylation

The N-terminal 17 amino acid motif of Htt is essential for intracellular localization,

turnover, and neurotoxicity (Zuccato and Cattaneo, 2010). Recent studies indicate that IKK

can phosphorylate two Ser residues (S13 and S16) of Htt and potentially enhance the

turnover of WT HDx1 in culture models. Moreover, overexpression and cytokine-induced

activation of IKK

in rat striatal precursor cells promote the cleavage of WT Htt and

generate phosphorylated fragments of various lengths, which may be eliminated by

autophagy (Thompson et al., 2009). Abnormal IKK

-mediated phosphorylation and

turnover of WT Htt may become detrimental, however, since WT Htt is important for

neuronal survival and BDNF expression (Zuccato and Cattaneo, 2010). An example is the

DNA damage-induced activation of IKK

, which promotes cleavage and depletion of WT

Htt (Khoshnan et al., 2009; Fig. 3). Interestingly, IKK

has no effect on the turnover of

mutant HDx1 and indeed phosphorylated mutant HDx1 accumulates in the nucleus, which

could promote neurotoxicity (Thompson et al., 2009). Recent studies indicate that mutant

HDx1 phosphorylated at Ser16 selectively accumulates in the nucleus of striatal neurons,

impairs nuclear export, and correlates with disease progression (Havel et al., 2011). Thus,

IKK

-mediated phosphorylation of mutant Htt may contribute to disease progression.

On the contrary, Truant et al. (personal communication) recently reported that inhibition of

IKK

by small molecules or shRNAs enhances the phosphorylation of Htt at its N-terminus

without affecting its turnover. While these opposing effects of IKK

on Htt phosphorylation

requires further clarification, it is intriguing that phospho-mimetic of Ser13 and Ser16 in

full-length mutant Htt imparts neuroprotection and ameliorates symptoms in HD mice (Gu

et al., 2009). However, it is unclear whether IKK

affects the phosphorylation of Htt

in vivo

or if these mutations affect Htt stability, intracellular transport, cleavage and

oligomerization. The rescue of pathology by mimicking phosphorylation and the findings

that IKK

inhibition could promote the phosphorylation of Htt further support the notion

that IKK

activation may be detrimental (Gu et al., 2009, Truant et al., unpublished data).

IKK

induced by elevated cytokines and abnormal levels of DNA damage could accelerate

the cleavage and turnover of WT Htt and deplete neurons of this pro-survival protein

(Khoshnan et al., 2009; Thompson et al., 2009). On the other hands if IKK

phosphorylates

mutant Htt, it may promote the nuclear accumulation of HDx1and induce pathology

(Thompson et al., 2009; Havel et al., 2011). Thus, further studies such as generating HD

mice with deleted IKK

in the CNS should reveal important information about the role of

IKK

in Htt phosphorylation and HD pathology.

The therapeutic potential of IKK

in HD

The prevailing evidence indicates that suppressing IKK

activity may impede disease

progression in HD. Inhibition of IKK

may lower neuroinflammation and the production of

inflammatory cytokines, which are considered as important modifiers of HD progression

(Björkqvist, et al., 2008). IKK

-dependent neuroinflammation is also implicated in PD and

AD and is mediated by caspases known to cleave Htt (Khoshnan et al., 2009; Burguillos et

al., 2011). Thus, lowering IKK

activity may dampen the toxic effects of

neuroinflammation, which is a component of several neurodegenerative disorders (Glass et

al., 2010). For HD, blocking of IKK

activity should also decrease the cleavage of WT and

mutant Htt and slow down the accumulation of oligomeric toxic fragments and neuronal

death induced by genotoxic insults (Khoshnan et al., 2009; Thompson et al., 2009).

Moreover, inhibitors of IKK

reduce the neurotoxicity of HDx1 in a brain slice culture

model of HD by yet an unknown mechanism (D. Lo et al. personal communication;

Khoshnan et al., 2004). Elevation of IKK

activity appears to promote nuclear localization

of HDx1 an event, which enhances neurotoxicity (Khoshnan et al., 2004; Thompson et al.,

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2009; Zuccato and Cattaneo, 2010). Thus, exploring the effects of IKK

inhibitors in animal

models of HD could lead to development of novel therapeutics.

While numerous IKK

inhibitors are available, their neuroprotective effects in disease

models are not well understood. Encouraging results have been obtained with a NEMO

Binding Domain (NBD) peptide, which corresponds to the C-terminus of IKK

and disrupts

the binding of IKK

to IKK

, preventing the assembly of an active complex (Madge and

May, 2009). Systemic administration of NBD blocks neurodegeneration, impedes microglial

activation in the substantia nigra, and improves motor function in a chemical mouse model

of PD (Ghosh et al., 2007). Subcutaneous injection of a selective inhibitor of IKK

also

protects dopaminergic neurons from LPS-induced neurotoxicity (Zhang et al., 2010).

Moreover, CNS delivery of a small molecule inhibitor of IKK

(BMS-345541) impedes

neurodegeneration in an ischemia model (Herrmann et al., 2005). NBD, chemical, and

genetic inhibition of IKK

prevents degeneration of medium-sized spiny neurons induced by

a mutant HDx1 (Khoshnan et al., 2004, D. Lo et al., personal communication). We have

identified IKK

inhibitors including the NBD peptide, which block DNA damage-induced

Htt cleavage, and improve survival in a human neuronal model (A. Khoshnan et al.,

unpublished data). Interestingly, these IKK

inhibitors also block caspase-6 activation,

which is a prominent enzyme in the pathogenesis of HD (Graham et al., 2006; Khoshnan et

al., 2009). These findings warrant the evaluation of IKK

inhibitors in HD animal models.

Several IKK inhibitors have entered clinical trials for their effects on malignancy (Lee and

Hung, 2008). These studies should reveal their safety and potency in human subjects and

potentially facilitate their application in HD patients. Considering the elevated levels of

inflammatory cytokines in the serum and CNS of pre-symptomatic HD patients (Björkqvist

et al., 2008), it will be interesting to see whether early systemic delivery of IKK

inhibitors

could affect the age of onset and disease progression in HD animal models.

The long-term systemic application of IKK

inhibitors however, may produce undesired

side effects considering the importance of IKK

in immune cell development and survival

(Hacker and Karin, 2006). Thus, strategies should be developed to selectively inhibit IKK

in the brain. An interesting therapeutic strategy is to knockdown the expression of IKK

the CNS by delivery of shRNAs, synthetic miRNAs, or anti-sense oligonucleotides

(Boudreau and Davidson, 2010). It is notable that deleting IKK

in the CNS of mice has no

visible effect on neurodevelopment, growth, and indeed ameliorates neurodegeneration in

ischemia and MS models (Herrmann et al., 2005; Van Loo et al., 2006). Moreover,

reduction of IKK

in the CNS prevents demylination induced by neurotoxic agents (Raasch

et al., 2011). Thus, long-term inhibition of IKK

in the CNS may not carry major deleterious

side effects. Silencing IKK

expression is protective in human neurons exposed to toxic

agents and prevents the activation of caspases, which cleave WT Htt (Khoshnan et al., 2009;

Thompson et al., 2009). Testing such strategies in animal models of HD are worthy of

investigation for efficacy, delivery and potential side effects.

Conclusions

While the role of IKK

in regulating NF-

B and promoting inflammation is well

characterized, elucidating NF-

B-independent functions of IKK

in the CNS and their

effects on neurodegeneration remains an important area of investigation. For HD, future

studies should focus on ablating IKK

in the CNS of animal models and observing disease

progression. This will elucidate whether disrupting the local activity of IKK

in the CNS

will affect the age of onset and HD progression. The presence of systemic inflammation in

HD years before the onset of symptoms is indicative of deregulated IKK

in the immune

cells and possibly other organs. Characterizing the role of IKK

in the immune system of

HD patients may provide insights into the complex nature of IKK

/Htt interaction and how

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dysregulation in this molecular switch may contribute to the development of early systemic

inflammation. The role of IKK

in regulating the phosphorylation of Htt is intriguing and

further studies are needed to unravel this aspect of IKK

in the neurobiology of Htt. Truant

et al. (personal communication), find that phospho-mimetics of Ser13 and Ser16 in the

mutant HDx1 induce a conformation that is less amenable to oligomerization and thus, less

toxicity. Further studies should uncover novel targets and a more efficacious route for

therapy and early intervention.

While these studies will take several years to accomplish, it is feasible to immediately

implement behavioral changes in HD patients, which could reduce IKK

activity

systemically and possibly lower the level of pro-inflammatory cytokines. One possible

avenue for therapy involves diet. It is known that daily food intake is substantially higher in

HD patients than in the normal population (Trejo et al., 2004). Moreover, excess food

intake, particularly high fat diet, is associated with IKK

-dependent neuroinflammation,

insulin tolerance, hypothalamic deregulation, and abnormal production of inflammatory

mediators in the CNS (Zhang et al., 2008). Thus, formulating diets enriched in natural

compounds with anti-inflammatory properties may help HD patients. Such modifications are

risk-free and may help to delay the onset and progression of HD.

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Fig. 1.

A schematic representation of canonical of IKK activation. The IKK complex is stimulated

from outside by factors like cytokines binding to the cell surface receptors and internally by

oxidative stress and DNA damage. Activated IKK phosphorylates I

, which promotes its

dissociation and degradation, liberating NF-

B to enter the nucleus and regulate gene

expression (Hacker and Karin, 2006).

Khoshnan and Patterson

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