Huntington's disease: An update of therapeutic strategies

Kumar, Ashok; Singh, Sandeep; Kumar, Vijay; Kumar, Dinesh; Agarwal, Sarita; Rana, Manoj Kumar

doi:10.1016/j.gene.2014.11.022

Cited by 57 publications

(67 citation statements)

References 72 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, gene-based therapies specifically for CB 1 or other single alterations in gene expression, will probably not be used clinically for HD in the near future because of the invasive nature of delivery and because the potential adverse effects of gene therapy are still being investigated. The more effective gene-based therapies for HD will target the underlying cause of the disease, the mHtt gene and encoded protein, and not secondarily lost cellular components (Kumar et al, 2015). In contrast, pharmacological strategies aimed at elevating CB 1 levels and/or signaling through remaining pool of CB 1 receptors has significant therapeutic potential for the treatment and management of HD.…”

Section: Introductionmentioning

confidence: 99%

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

et al. 2015

View full text Add to dashboard Cite

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB 1 ) decrease in the basal ganglia. Decreasing CB 1 levels are strongly correlated with chorea and cognitive deficit. CB 1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh Q7/Q7 ) or mutant huntingtin protein (STHdh Q111/Q111). Signaling bias was assessed using the Black and Leff operational model. Relative activity [DlogR (t/K A )] and system bias (DDlogR) were calculated relative to the reference compound WIN55,212-2 for Ga i/o , Ga s , Ga q , Gbg, and b-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, D 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and THC1CBD (1:1), and compared between wild-type and HD cells. The E max of Ga i/o -dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Ga i/o /Gbg bias and normalized CB 1 protein levels and improved cell viability, whereas CP55,940 and THC displayed b-arrestin1 bias and reduced CB 1 protein levels and cell viability in HD cells. CBD was not a CB 1 agonist but inhibited THC-dependent signaling (THC1CBD). Therefore, enhancing Ga i/o -biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are b-arrestin-biased-such as THC found at high levels in modern varieties of marijuana-may be detrimental to CB 1 signaling, particularly in HD where CB 1 levels are already reduced.

show abstract

Section: Introductionmentioning

confidence: 99%

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Presently available data indicate at the following mechanisms of mHtt toxicity: protein aggregation, excitotoxicity, oxidative stress, impairment of proteolysis and proteasome, enhanced apoptosis and autophagy, transcription regulation, including epigenetic mechanisms and mitochondria dysfunction [6,8,9,[18][19][20]. Although the functional relationship of Htt to mitochondria is still uncertain [21], it is becoming increasingly apparent that mHtt can impair mitochondrial function directly [22].…”

Section: Huntington's Diseasementioning

confidence: 99%

“…Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective.…”

Section: Huntington's Diseasementioning

confidence: 99%

“…Its domain model does not indicate any particular functions aside from domains that might mediate protein interactions. Indeed, numerous reports indicate that Htt interacts with above 200 proteins which represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, gene expression regulation and metabolism [8,[15][16][17].Presently available data indicate at the following mechanisms of mHtt toxicity: protein aggregation, excitotoxicity, oxidative stress, impairment of proteolysis and proteasome, enhanced apoptosis and autophagy, transcription regulation, including epigenetic mechanisms and mitochondria dysfunction [6,8,9,[18][19][20]. Although the functional relationship of Htt to mitochondria is still uncertain [21], it is becoming increasingly apparent that mHtt can impair mitochondrial function directly [22].…”

mentioning

confidence: 99%

See 1 more Smart Citation

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Karachitos¹,

Grobys²

2015

Pharmaceut Reg Affairs

View full text Add to dashboard Cite

It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

show abstract

“…While healthy individuals contain 16-20 repeats, more than 36 are present within the htt gene in HD patients [175]. Toxic protein aggregates are also seen in HD patients, whose brains contain accumulations of mutated HTT protein ( Figure 1D) [176]. The pathological hallmark of HD involves the loss of neurons in the cortex and striatum that lead to clinical manifestations including involuntary movements known as chorea, behavioral and psychiatric characteristics, and cognitive dysfunction.…”

Section: Parkinson's Disease and Huntington's Diseasementioning

confidence: 99%

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Peixoto¹,

Nunes²,

Rapôso³

2017

Mechanisms of Neuroinflammation

View full text Add to dashboard Cite

The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling appears to play a key role in inhibiting neuroinflammation and preventing the activation of a proapoptotic pathway, thereby promoting neural cell survival. In addition, evidence indicates that cGMP/protein kinase G (PKG) pathway is involved in the modulation of glial cell activity. Phosphodiesterase 5 (PDE5), which hydrolyzes cGMP in the inactive form, 5ʹGMP, is present throughout the body and brain and has emerged as a potential therapeutic target for diseases related to neuroinflammatory and neurodegenerative processes, since their inhibition leads to accumulation of cGMP. The objective of this chapter is to review current knowledge of NO/cGMP signaling pathways on neuroinflammation and the potential therapeutic use of PDE5 inhibitors (PDE5-Is) in neurological diseases. The extensive, while recent, literature on the effects of PDE-Is on Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and stroke has been reviewed.

show abstract

Huntington's disease: An update of therapeutic strategies

Cited by 57 publications

References 72 publications

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Contact Info

Product

Resources

About