Huntington’s Disease Associated Genes: Molecular Basis of Disease and Possible New Targets for Treatment

Special Article - Genetics of Huntington’s Disease

Austin J Genet Genomic Res. 2016; 3(1): 1022.

Huntington’s Disease Associated Genes: Molecular Basis of Disease and Possible New Targets for Treatment

Bhattacharyya NP*

BioMedical Genomics Centre, India

*Corresponding author: Nitai P Bhattacharyya, BioMedical Genomics Centre, PG Polyclinics (3rd Floor), 5 Suburban Hospital Road, Kolkata 700 20, India

Received: June 22, 2016; Accepted: November 11, 2016; Published: November 18, 2016

Abstract

Diverse molecular defects in Huntington’s Disease (HD) have been identified since the discovery of Huntingtin (HTT) gene mutated in the diseasein1993. Presently, there is no cure for the disease. To identify genes involved in HD pathogenesis, we collate data from diverse sources and using stringent criteria collected 523 HD associated genes. Enrichment analysis with these proteins revealed that diverse biological processes and pathways like gene expression, apoptosis, proteasomal degradation, glucose/carbohydrate metabolism, known to involve in HD pathogenesis, were significantly enriched. HD associated genes were significantly over represented in biological processes like cell cycle and differentiation indicating their possible role in HD pathogenesis. Comparisons of HD associated genes with targets of FDA approved drugs and probable protein targets having similar properties as that of FDA approved protein targets of drugs, we identified 49 HD associated genes that could be new probable drug targets. HD associated genes collected here will be useful to decipher molecular basis of HD including regulation of these genes and new targets for the treatment of presently incurable devastating HD.

Keywords: Huntington’s disease; Huntingtin interacting proteins; Coexpressed genes; Drug targets

Abbreviations

HD: Huntington’s Disease; FDA: Food and Drug Administration; AAO: Age at Onset; TVS: Target validation score

Introduction

Huntington’s Disease (HD, OMIM ID 143100), also well known as Huntington’s chorea, is an autosomal dominant progressive degenerative neurological rare disease (Orphanet ID ORPHA399), named after George Huntington, who first provided vivid systematic descriptions of the disease [1]. Typical characteristic of HD is abrupt involuntary movement (chorea) due to random muscle contractions. Other features of HD in early stage of the disease include behavioral changes like agitation, irritability, apathy, anxiety, dis-inhibition, euphoria, delusions, hallucinations, depression, dementia, cognitive decline and motor function impairment like eye movement abnormality, parkinsonian feature, dystonia, myoclonus, ataxia, dysarthria, dysphagia and spasticity with hyperreflexia. Dystonia or akinetorigid parkinsonian features supersede chorea with progression of disease [2,3]. HD is caused by expansion of normally polymorphic CAG repeats beyond 36 at the exon1 of the gene Huntingtin (HTT), also known as IT15 [4]. Manifestation of first symptoms, defined as the Age at Onset (AAO), is variable and normally ranges between 30 and 40 years. Early onset (<20 years, Juvenile HD) and higher age at onset (~70 years) have also been reported. The disease progresses slowly and within 15-20 years leads complete dependency in regular daily activities requiring full-time care and finally death. Common cause of death among HD patients is pneumonia and suicide. Other than classical symptoms, several features, which are not associated with the neuronal loss, complicate HD. These include weight loss and skeletal muscle loss. It is unclear whether such losses are secondary to neurological dysfunctions. However, such effects may contribute to the mortality or morbidity [5]. In spite of a large number of studies, since discovery of the gene that is mutated in HD since 1993, presently there is no cure for the disease.

Molecular mechanism of HD pathogenesis

Increase in length of glutamine (Q) stretch at N-terminal of HTT, coded by exon1 of the gene, alters conformation of the protein leading to cytoplasmic and nuclear aggregates, also known as Neuronal Intra- Nuclear Inclusions (NII). It is still debatable whether monomer of conformation modified HTT, oligomer of the mutant protein or aggregates are toxic [6]. Aggregate/NII is observed in cell models, brains of transgenic animals and post-mortem brains of HD patients [7]. Aggregate formation is enhanced with increase in number of Q in vitro and in vivo and is believed to cause neurodegeneration [8]. Contradictory result that visible aggregates are protective to neurons is also available. Intermediate oligomers or modified monomer of mutant HTT has been proposed to be toxic [9,10]. Autosomal dominant nature of the disease suggests a toxic gain of function of mutated protein that disrupts normal cellular functions and causes neuronal death [11]. Loss of function of wild type protein may also contribute, at least partially, to disease pathology [12]. It is now believed that both loss of wild type HTT and toxic gain of function of mutant HTT result in HD pathogenesis. Alterations of various cellular processes like excitotoxicity, oxidative stress, endoplasmic reticulum stress, axonal transport, ubiquitin proteasome system, autophagy and apoptosis are implicated in HD. Besides mitochondrial dysfunction and transcriptional deregulation have been also implicated in HD and reviewed [13-15]. The summary of diverse molecular alterations observed in many studies leading to neuronal death is shown pictorially in Figure 1.