The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both
Movement disorders are a group of nervous system disorders that primarily affect the basal ganglia and result in abnormal voluntary or involuntary movements. They are generally categorized as a group of neurological symptoms, signs, or diseases that manifest as either slowness or paucity of movement (hypokinesias; typically seen in Parkinson’s disease (PD) and other parkinsonian disorders) or by excessive, abnormal involuntary movements (hyperkinesias) typically seen in Huntington’s disease (HD), tremors, dystonia hemi-facial spasm, and akathisia [
Among all the movement disorders, PD affects approximately 2% of the population over the age of 65 and is characterized by behavioral motor deficits including tremor, rigidity, bradykinesia, and postural instability. Selective dopaminergic neuronal degeneration in substantia nigra pars compacta (SNpc) is the prominent feature of PD pathology [
The past decade has produced an exponential increase in research examining the genetic and environmental factors that contribute to the etiology of PD [
Recent investigations suggest that gene expression modulated by histone acetylation might be associated with neurodegenerative processes [
Histone acetylation is a chromatin modification that modulates histone-DNA interactions via two different classes of enzymes: HATs and HDACs (Figure
Transcriptional regulation by histone acetyltransferase and histone deacetylases. HAT: histone acetyltransferase, HDAC: histone deacetylases; HSP 70: heat shock protein 70, BDNF: brain derived neurotropic factor, GDNF: glial cell derived neurotropic factor, and PD: Parkinson’s disease.
In mammals the HDACs are divided into 4 classes based on their function and structural homologies to yeast HDACs. The classification of HDACs along with their pan inhibitors is provided in Figure
Histone deacetylases in brain.
HDAC class | Isoforms expressed in brain | Localization | Species | References |
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Class 1 (Zn2+ dependent) | HDAC 1 | Cortex, caudate/putamen, |
Human, |
[ |
HDAC 2 | Cortex, caudate/putamen hippocampus, amygdala SNpc, SNpr, locus coeruleus, gray matter, white matter, corpus callosum | Mouse, |
[ | |
HDAC 3 | Cortex, caudate/putamen hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidus | Mouse, |
[ | |
HDAC 8 | Hippocampus, amygdala SNpc, locus coeruleus | Human, |
[ | |
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Class IIa (Zn2+ dependent) | HDAC 4 | Cortex, caudate/putamen, hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidus | Human, |
[ |
HDAC 5 | Cortex, caudate/putamen, hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidus | Rat, |
[ | |
HDAC 7 | Cortex, caudate/putamen, hippocampus, amygdala SNpc, locus coeruleus, striatum, cerebellum | Rat, |
[ | |
HDAC 9 | Cortex, SNpc, hippocampus, amygdala | Human, |
[ | |
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Class IIb (Zn2+ dependent) | HDAC 6 | Cortex, caudate/putamen Hippocampus, amygdala, SNpc, locus coeruleus, cerebellum | Human, |
[ |
HDAC 10 | Cortex, amygdala, hippocampus | Human, |
[ | |
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Class IV (Zn2+ dependent) | HDAC11 | Cortex, hippocampus, brain stem, cerebellum, diencephalon | Human, |
[ |
SNpc: substantia nigra pars compacta, SNpr: substantia nigra pars reticulata, and HDAC: histone deacetylase.
Classification of histone deacetylase families. HDACs: histone deacetylases.
The isolation, purification, and identification processes of various HDAC isoforms begin right after the discovery of histone acetylation phenomenon. Thereafter, various HDAC inhibitors have been synthesized and studied which helps to explore the pharmacological actions of HDACs. A timeline figure regarding the historical aspects of HDACs has been provided (Figure
Historical aspects of HDACs and their modulators.
Initially, MPTP was identified as a strong neurotoxin when heroin addicts accidentally self-administered MPTP and developed an acute form of Parkinsonism that was indistinguishable from idiopathic PD [
Phenylbutyrate was among the very first HDAC inhibitors to be tested in MPTP model. Pretreatment of MPTP intoxicated mice with phenylbutyrate significantly attenuated the loss of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum. Moreover, phenylbutyrate also protects tyrosine hydroxylase (TH+) neurons from MPTP induced toxicity, which is basically a rate limiting enzyme in dopamine biosynthesis [
Neuroinflammation and oxidative stress have been well reported to play a key role in the pathophysiology of PD [
Olfactory and cognitive deficits have been reported very frequently in PD. A study shows that valproate pretreatment in rats infused with a single intranasal administration of MPTP was able to prevent olfactory discrimination and short-term memory impairments as evaluated in the social recognition and step-down inhibitory avoidance tasks. Moreover, valproate alone or in combination with lithium prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats [
As discussed earlier, MPP+ the toxic metabolite of MPTP acts by selectively inhibiting complex I of mitochondria. In a recent study, mitochondrial fragmentation was found to be an early event during apoptosis caused by MPP+ in SH-SY5Y cells. TSA selectively rescues mitochondrial fragmentation and cell death induced by lower doses of MPP+. The mitochondrial fragmentation occurring as a result of MPP+ treatment could possibly be mediated through downregulation of Mfn2. However, TSA administration results in complete reversal of Mfn2 expression. Further investigation suggests that TSA prevents MPP+-induced Mfn2 downregulation via inhibiting HDAC over Mfn2 promoter and alleviating its transcriptional dysfunction [
In their later study, Kidd and Schneider found the neuroprotective effects of valproate in MPTP intoxicated FVBn mice. Valproate partially prevents striatal dopamine depletion and almost completely protects dopaminergic cell loss in SNpc. These neuroprotective effects of valproate were attributed to its HDAC activity as increased acetylation of histone 3 lysine 9 was observed in SNpc of FVBn mice [
The majority of PD cases are sporadic; that is, only about 10% of patients report a positive family history [
The major complication in PD treatment with chronic L-DOPA is the occurrence of L-DOPA induced dyskinesias (LIDs). Various therapeutic strategies have been adopted to delay the use of L-DOPA as much as possible or by finding a suitable treatment option to reduce the dose of L-DOPA. However, none of these options fully serves the purpose and rendering LIDs, a major hurdle in PD treatment. However, recently, HDAC inhibitor, RGFP109, has been demonstrated to attenuate LIDs in the MPTP-lesioned marmoset [
The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable tool used in modelling PD in rodents. To target specific neurons and to bypass the blood-brain barrier, 6-OHDA is typically injected stereotactically into the brain region of interest. The classical method of intracerebral infusion of 6-OHDA involves a massive destruction of nigrostriatal dopaminergic neurons. Once it enters the brain, 6-OHDA accumulates in the cytosol where it is readily oxidized leading to the generation of reactive oxygen species and ultimately oxidative stress-related cytotoxicity. To date, 6-OHDA is widely used to lesion the nigrostriatal dopaminergic system as a model of PD [
As mentioned earlier, PD patients often experience cognitive impairment during the disease progression. Recently, Rane and colleagues studied the effect of sodium butyrate in 6-OHDA induced cognitive deficit in premotor stage of PD and they found sodium butyrate to be highly effective in attenuating cognitive deficits in 6-OHDA administered rats [
Rotenone is a strong inhibitor of mitochondrial complex I, which is located at the inner mitochondrial membrane and protrudes into the matrix. It has been demonstrated that the chronic systemic exposure to rotenone develops many features of PD, including nigrostriatal dopaminergic degeneration [
Neuroinflammation triggered by activated microglial cells results in deleterious events, that is, oxidative stress and cytokine-receptor-mediated apoptosis, which might eventually lead to dopaminergic cell death and PD progression [
As discussed above,
Although initial trials with valproate did not significantly alter Parkinson features in PD patients [
HDAC inhibition is a validated approach in cancer therapy, as evidenced by the FDA approval of vorinostat and romidepsin followed by encouraging clinical data from other HDAC inhibitors. Recent evidences reveal that HDAC inhibitors could play an important role in various brain diseases. Chronic dysregulation of the acetylation/deacetylation activities can ultimately lead to neuronal cell death as manifested in neurodegenerative diseases. Thus, more research is required to fully understand the precise mechanism(s) by which this system impacts neuronal survival. This study has summarised and described the most prevalent movement disorder, that is, PD that involve alterations in histone modifications which can be reversed, at least in part, by treatment with HDAC inhibitors. HDAC inhibitors have specific effects on gene expression, upregulating a selective set of target genes and reducing expression of others. The neuroprotective effects of various HDAC inhibitors are accomplished either through increased histone acetylation or through the increased transcription of genes encoding neurotropic factors (BDNF, GDNF), HSPs or reduction in the accumulation of neurotoxic proteins (
Neuroprotective mechanisms exerted by HDAC inhibitors. HSP 70: heat shock protein 70, BDNF: brain derived neurotropic factor, GDNF: glial cell derived neurotropic factor,
Alzheimer’s disease
Glycogen synthase kinase 3
Histone deacetylase
Histone acetyl transferases
Heat shock protein 70
Huntington’s disease
Parkinson’s disease.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are thankful to University Grants Commission—New Delhi, BITS—Pilani, and DST—New Delhi, for providing necessary facilities during the literature search for paper.