Huntington's disease: An update of therapeutic strategies

doi:10.1016/j.gene.2014.11.022

Gene

Volume 556, Issue 2, 10 February 2015, Pages 91-97

https://doi.org/10.1016/j.gene.2014.11.022 Get rights and content

Highlights

•
Genetic insight and molecular biology of the disease
•
Current management and therapeutics
•
Drugs against excitotoxicity

Abstract

Huntington's disease (HD) is an autosomal dominant triplet repeat genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation caused by abnormal CAG expansion within the htt gene on chromosome 4p16.3 is identified, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. There have been a number of therapeutic advances in the treatment of HD, such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (Tgasei). Although there is intensive research into HD and recent findings seem promising, effective therapeutic strategies may not be developed until the next few decades.

Introduction

Huntington's disease (HD) was first described by an American physician, George Huntington, in 1872 after he studied several affected individuals and also noted observations made by his father and grandfather (Neylan, 2003). It is an adult-onset, chronic and progressive neurodegenerative disease and clinically characterized by abnormal choreic involuntary movements and by psychiatric, psychological and intellectual disorders, and radiologically characterized by striatal atrophy of variable degree. Pathologically, in atrophied striatum, the normally predominant small projecting neurons are specifically affected. Since these neurons are inhibitory in function, their long axons terminate in the substantia nigra and use γ-aminobutyric acid (GABA) as a neurotransmitter and these GABA levels in the substantia nigra of HD are markedly low (Perry et al., 1973). On the other hand, dopaminergic nigral neurons remain intact in HD and the dopamine level in the HD striatum is higher than normal (Spokes, 1980). Therefore, HD is regarded as a relatively dopamine-predominant disease. In agreement with this finding, anti-dopaminergic drugs are clinically effective against choreic movements.

Section snippets

Genetic insight and molecular biology of the disease

HD is a single gene disease with autosomal dominant inheritance pattern and prevalence is about 5 in 100,000 worldwide (Clarke, 2005). Penetrance is almost 100% as individuals with the dominant allele eventually develop the disease. The average age of onset is 38 years, though the timing ranges from 25 to 70 years. However, approximately 5% of HD cases have presented before 20 years of age (Turnpenny and Ellard, 2007). Although the disease locus of HD was mapped to chromosome 4p16.3 by the G8

Current management and therapeutics

At this time, there is no cure for HD. The majority of therapeutics currently used in HD are designed to ameliorate the primary symptomatology of the HD condition itself (psychiatric agents for the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents) and thus and improve the quality of life of the patients (Handley et al., 2006a, Handley et al., 2006b). It is important to determine whether patients require treatment when they present. In the early

Conclusion and future directions

The genetics and some therapeutic advances in the management of HD have been discussed. Most of these therapies focus on the development of neuroprotective strategies, with the aim of delaying the onset and slowing the progression of HD. As the onset of neurodegenerative processes begin long before the clinical manifestations of HD, it is also important to develop laboratory methods of monitoring disease progression before the onset of clinical symptoms. Most of the advances discussed are still

Conflicts of interest

The authors have no financial conflicts of interest.

Acknowledgments

The authors are thankful to Sanjay Gandhi Post Graduate institute of Medical Sciences (SGPGIMS), Lucknow for providing infrastructure facility. Ashok Kumar is thankful to DBT-New Delhi (DBT-JRF 2009-10/515) for his fellowship.

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ReviewHuntington's disease: An update of therapeutic strategies

Highlights

Abstract

Introduction

Section snippets

Genetic insight and molecular biology of the disease

Current management and therapeutics

Conclusion and future directions

Conflicts of interest

Acknowledgments

Lancet

Lancet Neurol.

Neurobiol. Dis.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Neurobiol. Aging

Exp. Neurol.

Cell

Neuroscience

J. Biol. Chem.

Trends Neurosci.

Neurochem. Int.

Brain Res.

Semin. Pediatr. Neurol.

Neurosci. Lett.

Cell

Mol. Cell. Neurosci.

Exp. Neurol.

J. Biol. Chem.

Neurosci. Lett.

Cell

Neuron

Clinical experience with risperidone and memantine in the treatment of Huntington's disease

J. Natl. Med. Assoc.

Structural basis of DNA recognition by anticancer antibiotics, chromomycin A(3), mithramycin: roles of minor groove width and ligand flexibility

Biopolymers

Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease

Nat. Med.

Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release

Hum. Mol. Genet.

A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2–8 in the R6/2 transgenic mouse

Proc. Natl. Acad. Sci. U. S. A.

Neurological disease

Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neuritis in brain

Science

Green tea (−)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models

Hum. Mol. Genet.

Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease

J. Neurosci.

Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease

J. Neurosci.

Principles of Medical Genetics

Protein synthesis: translation and posttranslational modifications

Transglutaminases: nature's biological glues

Biochem. J.

Pharmaceutical, cellular and genetic therapies for Huntington's disease

Clin. Sci.

Pharmaceutical, cellular and genetic therapies for Huntington's disease

Clin. Sci.

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Proc. Natl. Acad. Sci. U. S. A.

Review
Huntington's disease: An update of therapeutic strategies