Kaynaat Sohail; Umm e Aiman; Noreen Samad

doi:10.19080/OAJNN.2020.13.555866

Review Article

Huntington Disease and Striatum: A Mechanistic Approach

Kaynaat Sohail, Umm e Aiman and Noreen Samad*

Department of Biochemistry, Bahauddin Zakariya University, Pakistan

Submission: March 06, 2020; Published: May 26, 2020

*Corresponding author: Noreen Samad, Department of Biochemistry, Bahauddin Zakariya University Multan-Pakistan

How to cite this article: Kaynaat S, Umm e A, Noreen S. Huntington Disease and Striatum: A Mechanistic Approach. Open Access J Neurol Neurosurg. 2020; 13(3): 555866 DOI: 10.19080/OAJNN.2020.13.555866.

Abstract

This study is a systematic review of the research, based on all possible pathways that include in Huntington Disease (HD). Electronic database, science direct and google scholar for relevant publications were searched. It is reported that striatum region is mainly affected in HD. Many pathways are involved in normal striatal signaling but in HD striatal microcircuits are damaged due to mutated htt protein. HD is being classified in inherited disorders or autosomal disease in middle age that cause irregular movements, psychiatric disorder, mental impairment and death occur after 15-20 years. Dopamine depleting drugs are known effected for its treatment, but no complete and proper medication is available for HD. The present review provides better mechanistic understanding related to direct and indirect pathways which are involved in progression of HD and future therapeutics.

Keywords:Striatum; Huntington’s disease; Neurodegenerative disease; Hereditary disorder; Genetic Mutation; Signalling pathways

Introduction

In life span of adulthood Huntington’s Disease (HD) is classified among considerable genetic disorders and it has acute effect on nervous system by agitate the underway physical and maniac effects[1].HD is an autosomal prevailing neurodegenerative illness described by mental unsettling influences and dynamic psychological decay identified with advancement of reflex chorea movements. The reason for HD is a genetic alteration which trigger polyglutamine (CAG) development in coding area of huntingtin (htt) gene [2]. Native description by George Huntington focus the clinical features of a hereditary developing neurodegenerative disorder starting in midlife with the characteristics of irregular movements, psychiatric disorder, mental impairment, with death occur 15-20 years after onset, and no specific treatment is available [3]. Dystonia, the involuntary contraction of muscles, is observed in most persons with HD but is more prominent in juvenile-onset individuals. As typical the progression of adult-onset of HD, straightforward chorea can develop into a more complicated constellation of movement disorders that progressively include dystonia [4]. Moreover, it is caused by the mutation of the gene that produces a protein called huntingtin (htt). The mutation depends on the continuous repetition of the trinucleotide CAG that in turn makes the protein toxic for the brain cells, as a result, the degradation of the neurons which carry the mutant protein [5]. The HD gene maps to chromosome 4p16.3. The molecular basis of HD is the expansion of CAG repeat in huntingtin gene. The size of these CAG repeat varies from 37 to 95 repeats [6].

Methodology

An extensive pursuit was led on the electronic databases, Science direct and PubMed/Medline and the writing was recovered utilizing web engines for the most part Google Scholar. As the focus was to search for progressively original data, the search was for the most part constrained to academic research articles that distributed in English. In excess of 100 research articles and reviews were specify out of which, 36 were chosen by study determination criteria. The extensive search was led amid March 2018 to April 2018.

Role of Huntingtin (htt)

Even though the function of normal htt is still not entirely defined, it is very early expressed in development and various lines of evidence evince that it has a function in vesicular trafficking, endocytosis and exocytosis [7-9]. The interruption of htt gene leads to the development of embryo lethality. [8] The mutation in native form (mhtt) compact the various fundamental pre-and postsynaptic proteins that are associated with vesicle transfer and control of synaptic make-up and receptors disguise [10-12].

Selective approach of striatum lesion

The initial targeted depletion of GABAergic inhibitory cell projections familiar with medium spiny neurons (MSNs) leads to the better recognition of Huntington disease by disintegration of neurons in areas of brain and cortex [13]. Rhes (Ras homolog enriched in striatum) is a small guanine nucleotide–binding protein (G protein) that is particularly localized to the striatum [14]. Rhes binds mhtt protein to elevate its cytotoxicity. The definite pathology of HD may consider the interaction between the striatal-selective G-protein Rhes and mhtt [15]. The most intriguing parts of Huntington’s disease pathophysiology is the perceptive defenselessness of explicit neuronal subtypes and although its continuous expression effect the whole nervous system [16,17]. Striatal decay is a property of pathologic component of Huntington’s disorder and being a segment of the basal ganglia, the striatum is engaged with activity, judgments and control towards regulation of movement, and the two direct and indirect important pathways emerge from striatal Sharp Projection Neurons (SPNs) [18,19] the direct pathway (dSPNs) manifest the receptor dopamine D1 that direct towards basal ganglia nuclei. Indirect pathways SPNs(iSPNs) display the D2 receptor that play role in regulating the basal ganglia structures via sub thalamic nucleus by sending the tensive projections towards globuspallidus parts of externa [20].

Organization of striatum microcircuit

Neocortex part of the brain extend to the doral striatum region that is involve in the motor and sensory functions by the projections of the glutamatergiccorticostriatum [21,22]. These excitatory cortical signs interface with glutamatergic contributions from midline thalamic cores and dopaminergic projections from the standards compact of the substantianigra [23] The excitory cortical signals play role in accommodating the coupling of sensory contributions with data on development sequences [24-26]. The interactions of pathways that are take place in MSNs provide efficient data organization that is vital for striatal control of propensity development and motor-based learning [27].

Pharmaceutical medication preferences

Numerous components and surgical techniques can surveying in HD for their viability in restrain chorea, and chemical base dopamine rivals, acetyl cholinesterase inhibitors, glutamate blockers, benzodiazepines antagonist used for the therapy and dopamine-exhausting operators and dopamine agonists, and ant seizure drugs based on lithium, cannabinoids, effective in treatment of Huntington’s disease the extensive techniques like fetal cell transplantation and profound brain stimulation also play role for the treatment of Huntington’s disease [28,29]. Dopamine is freed in the striatum from nigrostriatal terminals and is neurotoxic after direct shot into the striatum [30]. A hyperactive dopaminergic framework could help to choric side effects and imply in neurotoxicity of HD [31] Tetrabenazine (TBZ), play role in the integration of dopamine signaling pathways by a dopamine path inhibitor that diminishes striatal cell damage and decrease the motor movement disorders and by administration of TBZ in mice the ensurement of improved movement in pathogenesis of Huntington’s disease take place [32,33]. TBZ specifically display more dopamine than norepinephrine [29,34]. The greatest restricting areas of the brain for the binding of TBZ for the treatment of Huntington’s disease take place in the caudate part of nucleus, accumbenssepti, and letiform of outer brain core [35,36]. The administration of TBZ leads to the cause of sedated Parkinson disease, depression and akathisia but Food and Drug Administration highly regard TBZ for the treatment of chorea linked with Huntington’s disease [29,34] Pharmacological contribution normally denotes the hyperkinetic development disorder that may identify with HD, for example, myoclonus, chorea, ballism, tics and dystonia[33] While choosing an intercession, suppliers ought to analyze if there will be a positive or negative outcome of the operator on mental issues related with HD, for example, mania, anxiety, lack of concern, touchiness, obsessive– compulsive disorder, or psychological decrease cognition. Adjunctive treatments substitute, and behavioral plan, integral treatments, and cognition based intellectual mediations additionally may assume a part in clarifying the indications of HD and should be incorporated while choosing meds. Huntington’s disease is neurodegenerative disease cause by the genetic mutations in which striatum portion of the brain is majorly affected due to mutated Huntington protein(mhtt) [36]. The mutated protein affects the normal pathways in the brain that cause many mental and physical abnormalities. HD starts from midlife and can cause death and if effective treatment not carried then it draws more attention towards Huntington’s diseased individuals. The complete knowledge of the striatal neuron vulnerability and all the pathways involve in HD may give greater understanding for designing suitable medications and any future clinical trials for HD [23,24].

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