Template for Electronic Submission to ACS Journals 17 © 2023 Datta, Neelabh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits the user to copy, distribute, and transmit the work provided that the original authors and source are credited. Molecular Mechanisms and Clinical Features of Hunting- ton Disease: A Fatal Neurodegenerative Disorder with Au- tosomal Dominant Inheritance Neelabh Datta1 1Department of Biochemistry, Asutosh College (Affiliated to University of Calcutta), 92, Shyama Prasad Mukherjee Rd, Kolkata, West Bengal, 700025, INDIA KEYWORDS: Huntington’s disease, neurogenetics, molecular mechanisms, pathophysiology, therapy ABSTRACT: Huntington disease (HD) is a fatal genetic disorder that affects the movement and cogni- tion of affected individuals. It is inherited in an autosomal dominant manner, meaning that each child of a parent with HD has a 50% chance of inheriting the mutated gene. The mutation involves an expan- sion of a trinucleotide repeat (CAG) in the HD gene, which is located on the short arm of chromosome 4p16.3. The HD gene encodes a protein called huntingtin, which has an unknown function. The number of CAG repeats determines the severity and onset of the disease. Normal individuals have 26 or fewer repeats, while HD patients have 40 or more repeats. Individuals with 27 to 35 repeats do not develop HD, but they can pass on the mutation to their offspring, especially if the mutation is inherited from the father. Individuals with 36 to 39 repeats may or may not develop HD, depending on other factors. The more CAG repeats, the earlier the symptoms appear. HD is the most extensively studied neurodegen- erative disorder with a genetic cause. There are genetic tests available to diagnose HD and to predict the risk of developing HD in asymptomatic individuals. There are also prenatal and preimplantation tests to prevent the transmission of HD to the next generation. HD is characterized by involuntary movements called chorea, which affect all muscles and impair all psychomotor functions. HD patients also suffer from cognitive decline and psychiatric symptoms, such as mood disorders and social changes. These symptoms are chronic and progressive, leading to complete dependence and death. Chorea can also be caused by other conditions, such as metabolic disorders or drug-induced side ef- fects. Neuroimaging techniques, such as MR imaging, fluorodeoxyglucose positron emission tomogra- phy (FDG-PET), MR spectroscopy, and diffusion tensor imaging, can help to diagnose HD and monitor its progression. The pathophysiology of HD involves the loss of neurons and the dysfunction of neuro- transmitter systems, especially the dopaminergic system. There is no cure for HD, but there are treat- ments to manage the symptoms and to improve the quality of life of HD patients. These include phar- macological interventions, such as dopamine receptor antagonists or depleters, and non- pharmacological interventions, such as psychological and social support. HD is a devastating disease that poses many challenges for patients, families, and healthcare providers. There is hope that gene- targeted therapies will be developed in the near future to stop or slow down the disease process. INTRODUCTION Huntington disease (HD) is a fatal neuro- degenerative disorder that affects the CNS and causes motor, cognitive, and behaviour- al problems in the patients [1]. The disease is inherited in an autosomal dominant man- ner and is caused by a mutation in the Htt gene that results in an expansion of the polyQ domain of the Htt protein beyond 36 glutamines [3]. The brain cells of HD patients have misfolded polyQ Htt proteins that form Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 18 clumps, unlike the normal individuals who have diffuse localization of Htt [12]. The length of the polyQ expansion determines how fast the aggregation occurs [13]. The normal function of the cell to recycle and de- grade proteins and produce energy is dis- rupted by the misfolded polyQ Htt, which al- so binds to other proteins such as CREB binding protein and depletes them from the cell [14]. This leads to a toxic effect of the mutant Htt, but it also affects the normal function of the wildtype Htt, which does not have the polyQ expansion [2, 15]. Therefore, any treatment for HD must consider both the gain-of-function and the loss-of-function ef- fects of the mutant Htt. The age of onset of HD depends on the length of the polyQ ex- pansion, with longer expansions causing earlier and more severe symptoms [4]. The polyQ length explains 60-70% of the varia- tion in the age of onset, while the rest is in- fluenced by environmental and genetic fac- tors [5]. The main feature of HD pathology is the death of the GABAergic MSN in the striatum, which is a part of the brain that controls movement and cognition [2, 6]. The death of the MSN is accompanied by inflammation and activation of glial cells, which are the support cells of the CNS [2]. Microglia, which are the immune cells of the CNS, are acti- vated in both early and late stages of HD and cause damage to the neurons in the striatum and cortex [7]. Astrocytes and oli- godendroglia, which are the cells that pro- vide nutrients and insulation to the neurons, are also increased in HD brains, especially in the globus pallidus and the white matter sur- rounding it [8]. HD patients also show a sig- nificant loss of brain volume in different re- gions, such as the cerebral cortex, the telen- cephalic white matter, the putamen, and the caudate nucleus [2, 9, 11]. The loss of brain volume can be detected even before the symptoms of HD appear, indicating an early degeneration of the brain [10]. HD is a dis- ease that affects the whole brain and causes progressive deterioration of the patients' functions and quality of life. There is no cure for HD, and the current treatments are only palliative and symptomatic. Structure of the Huntingtin Protein The huntingtin (Htt) protein is a molecule that is found in humans and other vertebrates, and it has a very similar structure and func- tion among them [2,16]. It is a big protein, with a molecular weight of about 350 kDa, and it has a shape that is long and flexible [17,18]. The protein is made up of many re- peated units called HEAT (Huntingtin, Elon- gator factor3, PR65/A regulatory subunits of PP2A, and Tor1), which help the protein to interact with other proteins and to form com- plex structures [2,24]. One of the special fea- tures of the Htt protein is that it has a region near the beginning of the protein that con- tains many glutamine residues, which are amino acids that have a nitrogen atom in their side chain [2]. This region is called the polyQ tract, and it starts from the 18th amino acid in the protein [2]. The number of gluta- mines in the polyQ tract can vary a lot, and this can affect how the protein works and how easily it dissolves in water [27,30]. In most people, the polyQ tract has around 20 glutamines, but in some people, it can have more than 40 glutamines, and this can cause a brain disease called Huntington's disease (HD) [20,21,22]. The polyQ tract is sur- rounded by another region that has many proline residues, which are amino acids that have a ring-shaped side chain [31]. This re- gion is called the polyP tract, and it helps the protein to stay dissolved in water and to in- teract with proteins that are involved in mov- ing things inside the cell [31,32]. The polyQ tract is not present in all animals that have a similar protein to Htt, but it is very important for the brain functions of animals that have it, Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 19 as shown by experiments with mice that do not have the polyQ tract [2,29]. The polyQ tract can also form structures that look like zippers, and these structures can bind to other parts of the protein or to other proteins that have similar structures [2,28]. The Htt protein is therefore a very complex and ver- satile protein that is involved in many differ- ent processes in the cell. The way that HD is inherited and how it affects different people is related to the way that the polyQ tract can change in size and cause problems, which is caused by an increase of the number of re- peats of three nucleic acids (C, A, and G) in the first exon of the HD gene, which is locat- ed on chromosome 4p16.32 [19]. Htt has various features that allow it to move between the nucleus and the cytoplasm of the cell [2]. It has a nuclear export signal (NES) at the end of its C-terminal domain, which enables it to exit the nucleus [33]. It also has a domain at the beginning of its N- terminal domain, which consists of 18 amino acids and interacts with TPR, a protein that is part of the nuclear pore complex and facili- tates nuclear import [33]. This domain also forms a membrane-binding domain that has an amphipathic alpha helical structure and can reversibly bind to different types of vesi- cles, such as those derived from the endo- plasmic reticulum (ER), endosomes, and au- tophagosomes [34]. This domain is essential for the normal function of Htt, as mutations or deletions in this region cause Htt to accu- mulate in the nucleus and induce cellular toxicity [33]. Htt is also subject to proteolytic cleavage by various enzymes, such as caspases and calpains, which are conserved among higher vertebrates [35]. These en- zymes generate fragments of Htt that are found in the nucleus, but their role is unclear. The proteolysis of Htt is influenced by the cellular context, as it is increased in dis- eased brains and more selective for the fragments that have the N- and C-terminal domains, especially in the striatum [2,36]. Another enzyme that can produce N-terminal fragments of Htt is cathepsin, which belongs to the lysosomal degradation pathway [37]. Htt can also undergo different types of post- translational modifications in its N-terminal region, such as ubiquitination, sumoylation, and phosphorylation by kinases like Akt, ERK1, and Cdk5 [2,38]. The phosphorylation level of Htt is regulated by S/T phosphatases PP1 and PP2A [39]. Furthermore, Htt can be palmitoylated in its N-terminal region through the interaction with Huntingtin-Interacting Protein 14 (HIP 14) [40]. Palmitoylation is a mechanism that is used by several proteins that are involved in vesicle trafficking to maintain their proximity to the plasma mem- brane [2]. Htt is highly expressed in the hu- man brain and testes [41]. In the brain, it is present in both neurons and glial cells [42]. Htt has a complex subcellular localization pattern, which may depend on its conforma- tional state, as different antibodies that rec- ognize different epitopes within the protein show different subcellular staining profiles [43]. Htt is not only localized in the nucleus, ER, and Golgi complex, but also in the axons and synapses of neurons [41], where it is associated with microtubules, caveolae, and synaptosomes [41]. Significance and Function of the Hunting- tin Protein The function and role of the huntingtin pro- tein is still unclear, despite the fact that its genetic location was identified a long time ago. Some studies have proposed that hun- tingtin is involved in regulating gene expres- sion and transporting molecules inside the cell, based on its presence in both the cyto- plasm and the nucleus and its frequent inter- actions with other proteins [44]. The hunting- tin protein also plays a role in neuronal de- velopment, synaptic transmission, axonal transport, and autophagy [51]. The huntingtin Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 20 gene has a segment of DNA that repeats the sequence CAG, which codes for the amino acid glutamine. In normal huntingtin proteins, this segment has less than 27 repeats, and people with 27 to 35 repeats (called transi- tional alleles) [45] do not develop the dis- ease, but they may pass on longer repeats to their offspring. People with 36 or more re- peats will develop the disease [46]. The number of CAG repeats tends to increase in each generation, which means that the dis- ease becomes more severe and appears earlier in life. This phenomenon is called "an- ticipation" [47]. The age of onset of the dis- ease is inversely related to the number of CAG repeats. Therefore, people with juve- nile- and infantile-onset HD have more re- peats than their parents and show symptoms earlier [48]. The huntingtin protein is expressed in many different types of cells, but it is especially abundant in the brain and the testes, and to a lesser extent, in the liver and the lungs [49]. It has a protective role against cell death, but when it is mutated or underex- pressed, it causes early apoptosis and dys- function. The mutation that causes HD is an expansion of the CAG repeats, which results in a longer stretch of glutamine in the protein [46]. This leads to the formation of abnormal aggregates of the protein in the nucleus and the cytoplasm of the cell, which disrupts the normal balance of the cell and triggers apop- tosis [50]. The aggregates also interfere with the normal function of huntingtin and its in- teracting partners, leading to neuronal de- generation, inflammation, oxidative stress, mitochondrial dysfunction, and impaired au- tophagy[52]. The most affected brain region is the striatum, which is involved in motor control and cognition, followed by the cortex, which is responsible for higher cognitive functions [53]. The symptoms of HD include chorea, dystonia, rigidity, bradykinesia, cog- nitive impairment, and psychiatric disturb- ances [54]. There is no cure for HD, but some treatments can help to manage the symptoms and improve the quality of life of the patients [55]. Clinical Indicators of Huntington Disease HD affects the different aspects of behav- iour, cognition, and motor function of hu- mans [51]. The disease has three subtypes, depending on the age of onset: adult-onset, juvenile-onset, and infantile-onset. The most common subtype is adult-onset HD, which usually manifests in the fourth or fifth decade of life. Patients with adult-onset HD experi- ence a range of behavioural symptoms, such as irritability, agitation, loss of inhibition, and aggression, which often precede the motor symptoms [46,52]. The motor symptoms in- clude involuntary movements (chorea), which become less prominent as the disease progresses and are replaced by rigidity and abnormal muscle contractions (dyskinesia). Patients also lose their ability to maintain a sustained voluntary muscle contraction and their fine and gross motor skills, leading to severe disability and dependence [46,52]. The cognitive symptoms include impairment of memory, executive function, language, and visuospatial skills, which worsen over time and result in dementia [51]. The disease course of adult-onset HD is typically 15–20 years from the onset of symptoms to death [51]. The other two subtypes, juvenile-onset and infantile-onset HD, are much rarer and account for about 10% of HD cases. They are characterized by an earlier onset of symptoms, usually before the age of 20, and a more rapid progression of the disease [46,53]. The main features of these subtypes are rigidity, dyskinesia, and cognitive de- cline, with little or no chorea [46,53]. These patients often show signs of motor deteriora- tion and poor academic performance before they are diagnosed [46,53]. Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 21 Genetic Modifiers of Huntington’s dis- ease The discovery of the HD defect [54] prompt- ed many researchers to investigate the role of HD genes that were chosen based on their functional relevance. However, a new approach emerged in the early 21st century, which was based on two major advances in human genetics: firstly, the identification of common genetic variations across the ge- nome, known as single nucleotide polymor- phisms (SNPs), and secondly, the develop- ment of oligonucleotide array technology, which enabled the simultaneous genotyping of hundreds of thousands to millions of SNPs for unbiased genetic studies [55]. This ap- proach, called genome-wide association analysis (GWA), allowed the researchers to scan the entire genome for genetic factors that influence the HD phenotype, without re- lying on prior knowledge of gene function. To apply this approach to HD with sufficient sta- tistical power, three additional requirements had to be met: firstly, the availability of ge- nomic DNA from a large number of HD sub- jects for genotyping; secondly, the definition of a robust phenotype that accounted for the effects of the CAG repeat size, which is the main determinant of the HD phenotype; and thirdly, the exclusion of any potential modifier factors that are linked to HTT and act in cis to modify the effect of the mutation, as these factors would confound the genome-wide search [55]. Statistically assessing the relationship be- tween the length of inherited CAG repeats and the age of motor onset provided a vigor- ous HD phenotype that accounted for the effect of CAG repeats. Due to the danger of including inexplicably influential outliers, the analysis was limited to CAG repeat lengths typical of adult-onset (40 to 53–55) and suffi- cient representation of subjects to guarantee consistent results [56]. Based on their inher- ited CAG repeat lengths, >90% of HD sub- jects met these criteria, allowing a standard curve to be produced that relates CAG re- peat size to average age-at-onset. In the ab- sence of the effects of the CAG repeat size, an evaluation of this expected age-at-onset with the individual's observed age-at-onset provided the phenotype for analysis of ge- netic effects on onset [57]. It was fundamen- tally a matter of subtracting the expected age-at-onset from the observed age-at-onset to obtain the test phenotype, or residual age- at-onset, which was either a positive or neg- ative number of years based on whether the subject's onset was later or earlier than an- ticipated. It was possible to test whether ge- netic variations at the HTT locus other than the CAG repeat size affect age-at-onset by using residual age-at-onset as a relevant HD phenotype and several thousand unrelated HD subjects [55]. In order to examine this, common single nucleotide polymorphisms (SNPs) were compiled across the gene and defined as haplotypes (i.e. the linear array of alleles at multiple SNPs along the chromo- some, conducted as a physically linked set to progeny—basically a digital fingerprint for the HTT region) [55]. In addition, expanded CAG alleles associated with HD were found in multiple haplotypes, indicating that multi- ple independent ancestral HD CAG expan- sion mutations contributed to the contempo- rary population of HD individuals [58]. The most common haplotypes, representing more than 83% of HD subjects, were not re- lated with differences in onset age, which suggests that genetic factors usually act in transfer through genes detached from HTT [58]. Accordingly, HD is viewed as a proto- typical autosomal dominant genetic disorder based on whether it is passed on to progeny (or not), but the timing of disease onset is actually polygenic, determined by the combi- nation of CAG repeats and other genetic fac- tors. Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 22 Factors that play a role in the develop- ment of HD 1. Mitochondrial disorder In early studies, functional abnormalities in mitochondria were discovered, indicating that mitochondrial dysfunction plays an es- sential role in the pathogenesis of HD and this is usually seen in the early disease pro- cess. The caudate and to a lesser extent the cortex of post-mortem HD brains have suc- cinate dehydrogenase deficiency, a compo- nent of both the Krebs cycle and the electron transport chain's complex II. As compared to levels in matched control brains, HD brains demonstrated a significant decrease in com- plex II activity in the caudate nucleus (rough- ly 50%) [67]. In addition to reductions in complex II activity, complex III activity in the caudate and putamen, as well as complex IV activity in the putamen, have decreased as well [67]. In spite of this, since most of these patients suffered from advanced neuropathy, including severe striatal atrophy (pathologi- cal grades 3 and 4 of HD), mutations in mi- tochondrial sources (i.e., glial, neuronal, etc.) may have occurred [59]. 2. Oxidative stress due to ROS Reactive oxygen species (ROS) are pro- duced in excess in the body, which results in oxidative stress when the body is unable to detoxify them and repair the damage they cause. Animal models with HD showed in- creased levels of malondialdehyde, 8- hydroxydeoxyguanosine, 3-nitrotyrosine, and heme oxygenase oxidative damage prod- ucts, and free radicals in the areas of de- generation in the brain of HD affected indi- viduals which propose that oxidative stress is connected with the disease, either as a pri- mary event or a secondary component of the cascade processes of cell death [67]. There is ample evidence that oxidative damage subsidizes significantly to the pathogenesis of neurodegenerative diseases such as HD [60]. 3. Apoptosis There is a link between the pathogenic mechanism of apoptosis and chronic neuro- degenerative diseases like HD [61]. Caspa- ses are cysteine-dependent, aspartate- specific proteases that initiate and execute apoptosis. A transcriptional up regulation of caspase-1, caspase-3, and caspase-9 in HD patients as well as in animal models of HD has been reported [62]. Amyloidogenic Mu- tant Huntingtin (MHtt) has been confirmed to induce apoptosis in HD patients [63]. 4. Neuroinflammation By discharging cell mediators that combat foreign substances and prevent infections, the inflammatory process safeguards our bodies from harm and disease. Neuroin- flammation does not directly correlate with HD progression, despite inflammatory pro- cesses being evidently confirmed in its path- ophysiology. Post-mortem studies of degen- erating neurons in HD have discovered high levels of activated microglia and macro- phages as well as elevated levels of IL-6, IL- 1, and TNF- in the plasma and striatum of HD patients [67]. Microglial cells may identify the pathogenic mHTT aggregates as foreign substances, resulting in neuro-inflammation [64]. 5. Neurotoxicity Disproportionate glutamate neurotransmis- sion leads to excitotoxic neuronal death, which is supplemented by insistent intracel- lular calcium level elevation [65]. As NMDA (N-Methyl-D-aspartic acid) receptors are over activated by excited amino acids, free radicals are formed and mitochondrial per- Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 23 meability transition pores are unlocked, both of which are lethal. The role of neurotoxicity has been documented as significant since the undeviating injection of acids such as QA and kainic acid causes neuro-degeneration of GABAergic MSN in HD [66]. Advances in Huntington's Disease Thera- py The HTT gene mutations that cause HD are still not fully understood, but research on the molecular mechanisms behind them is very promising and could lead to a cure. Current- ly, there are no neuroprotective therapies that can prevent or slow down the disease, and the only treatments available are symp- tomatic [67]. One of the main causes of HD is the toxicity of mHTT, the mutant form of the HTT protein, which is produced by the mutated gene. Therefore, reducing the ex- pression of mHTT, either by lowering the levels of HTT mRNA or the protein itself, is a potential strategy to treat HD [68]. Some studies have suggested that gene-silencing techniques that target the CAG repeats in the HTT gene, which are responsible for the mutation, could improve the functional, motor and cognitive outcomes of HD patients, but not their weight loss [67, 69]. These tech- niques involve using different types of DNA- binding elements, such as zinc-finger pro- teins, nucleases, epigenetic modulators, or transcription factors, to either block, disrupt, or correct the mutant gene. For example, zinc-finger transcriptional repressors can bind to the DNA and prevent its transcription, while zinc-finger nucleases can cut and edit the DNA [67,70]. Another example of a ge- nome editing technique is CRISPR/Cas9, which can also target and modify the HTT gene. These approaches have the ad- vantage of permanently correcting the CAG expansion that causes HD. Another way of reducing mHTT expression is by using anti- sense oligonucleotides (ASOs), which are synthetic molecules that bind to the HTT mRNA and trigger its degradation by an en- zyme called RNase H1 [71]. ASOs can reach the central nervous system without needing a viral or lipid carrier, and they are easy to develop [67]. A clinical trial by Tabrizi et al [72] used an ASO called IONIS-HTTRx to lower the levels of mHTT in the cerebrospi- nal fluid of 34 HD patients, who received doses ranging from 10 to 120 mg, and com- pared them with a placebo group. The re- sults showed that the mHTT reduction was dose-dependent [72]. A similar method of post-transcriptional gene suppression is RNA interference (RNAi), which uses non- coding double-stranded RNA sequences to silence specific genes. RNAi can be achieved by using different types of RNA molecules, such as siRNAs, shRNAs, or arti- ficial miRNAs, which have been shown to reduce the HD symptoms [67]. RNAi is also a promising technique for many other dis- eases. One of the main approaches for treating HD is to reduce the synthesis of the mutant HTT (mHTT) protein, which forms toxic aggre- gates in the brain. This can be achieved by using RNA interference (RNAi) techniques, which involve the use of small RNA mole- cules that bind to the mHTT mRNA and pre- vent its translation. Several types of RNA molecules have been used for RNAi, such as short hairpin RNA (shRNA), small interfering RNA (siRNA), and microRNA (miRNA) [67]. These molecules have been delivered to the brain of HD animal models using viral vec- tors, such as adeno-associated virus (AAV), which contain enhancers and promoters to drive the expression of the RNA molecules. The first trials of RNAi for HD were per- formed in rodents two decades ago. It is seen that shRNA targeting mHTT reduced its synthesis and prevented the formation of in- clusions, gait deficits, and rotarod dysfunc- tion in mice, in recent studies [67]. Similarly, Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 24 siRNA injected into the mouse striatum pro- longed the survival of striatal neurons, re- duced mHTT aggregates, and prevented motor dysfunction [73]. These results were replicated in multiple animal systems, such as rats, monkeys, and sheep [74]. A recent study used a single-stranded siRNA (ss- siRNA) for RNAi and achieved a selective decrease of CAG-expanded HTT protein in various regions of the mouse brain [75]. An- other type of RNA molecule that has been used for the suppression of mHTT is miRNA, which is a natural regulator of gene expres- sion. MiRNAs have been shown to have promising effects in genetically modified mice with HD; for example, one study re- ported that miRNA-mediated knockdown of mHTT prevented regional cortical and striatal atrophy and reduced weight loss [76]. Most of the RNAi techniques do not com- pletely eliminate the production of mHTT, but only reduce it to a certain extent. Therefore, another possible therapeutic approach is to overexpress the wild-type HTT, which may have a protective role against the toxic ef- fects of mHTT. Early trials of this strategy showed that inserting the wild-type HTT into mammalian cells that expressed mHTT re- duced cell death [77]. Several natural and synthetic compounds have been suggested as potential candidates for the treatment of HD and other neurodegenerative disorders. One of the most widely studied compounds for HD is tetrabenazine (TBZ), which is an inhibitor of the vesicular monoamine trans- porter 2 (VMAT2) that blocks the uptake of dopamine into vesicles [67]. TBZ has been shown to exert antichorea effects in patients with HD and was the first approved drug for the disease [78]. However, TBZ has some limitations, such as low bioavailability and adverse effects. Therefore, studies have been conducted to optimize the drug delivery and bioavailability of TBZ using nanotech- nology techniques, such as nanoparticles and nanocapsules [79]. Another class of compounds that may have beneficial effects for HD are flavonoids, which are natural pol- yphenolic compounds found in plants. Fla- vonoids have been shown to reduce cellular stress and exert anti-inflammatory and anti- apoptotic effects in the cell [80]. Some ex- amples of flavonoids that have been tested for HD are resveratrol, curcumin, and quer- cetin. Marine compounds have been proposed as potential sources of novel drugs for HD and other neurodegenerative diseases. Marine compounds have diverse chemical struc- tures and biological activities, such as anti- oxidant, anti-inflammatory, and anti-apoptotic properties. Some examples of marine com- pounds that have been investigated for HD are fucoidan, xyloketal B, fucoxanthin, and cerebrosides [67, 81]. A recent study sug- gested that pridopidine, a dopamine stabi- lizer, may be a promising drug for HD symp- toms. Pridopidine acts on the sigma-1 recep- tor, which is involved in the regulation of cal- cium homeostasis, mitochondrial function, and neuroprotection. Pridopidine has been shown to improve motor and cognitive func- tions in HD animal models and patients [82]. The stage of Huntington's disease (HD) is related to the amount of dopamine in the central nervous system, since dopaminergic conduction disorders are the main cause of HD. Pridopidine, a drug that protects nerve cells from degeneration, has shown promis- ing results in animal models [83]. Drug treatment for HD has the advantage of being based on well-studied active compounds that are effective and tolerable for other similar neurodegenerative diseases [67]. This makes it easier to personalize the medica- tion according to the patient's diagnostics. Another potential treatment for HD is cell re- placement therapy using stem cells, which could reduce the symptoms of the disease [84]. Moreover, exercise and physical activity Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 25 have been reported to have positive effects on the motor function, gait speed, balance, and social well-being of HD patients [67, 85]. Therefore, exercise could be a complemen- tary therapy for HD. A novel approach to tar- get the underlying cause of HD is the use of monoclonal antibodies that bind to the mu- tant huntingtin (mHTT) protein and lower its concentration in the cell. This could prevent the mHTT from spreading and causing dam- age to the brain [84]. Gene therapy: A Possible Treatment of HD in the Future Research into gene therapy has led to the most exhilarating and favorable advances in HD research. A potential therapy for domi- nant genetic disorders, silencing mutant genes can offer major benefits. It is generally believed that gene therapy could have a two- fold effect: (i) restoring function to non-dead, but dysfunctional neuronal circuits, and (ii) protecting against disease progression [86]. As a matter of fact, gene therapy will not be used to treat disease, but to prevent it - to eliminate symptoms entirely. Molecular gene therapy targets the transcription and transla- tion processes of DNA into mRNA (messen- ger RNA) by a process called transcription and the synthesis of proteins using the in- formation in mRNA (a process called transla- tion) [87]. Antisense oligonucleotides (ASOs), zinc finger proteins, and RNA inter- ference techniques are three common meth- ods for gene-silencing [88]. Zinc finger pro- teins suppress transcription, antisense oligo- nucleotides suppress translation of mHTT, and RNA interference blocks protein transla- tion [89] In large neuroimaging studies per- formed during preHD, measurable measures of brain regions such as the striatum have been found to be excellent biomarkers of disease progression and will be useful in fu- ture gene therapy trials [90]. CONCLUSION Research indicates that the pathology of Huntington's disease (HD) may be signifi- cantly influenced by the loss of function in the normal Htt protein, despite the disease primarily being attributed to a toxic gain of function caused by the expansion of polyglu- tamine (polyQ) sequences. The Htt protein is known to interact with various effector pro- teins and is involved in critical cellular pro- cesses such as transcription and intracellular trafficking. These interactions and processes are vital for the proper processing and locali- zation of numerous proteins. Consequently, a deficiency in Htt function could potentially have a more extensive impact on cellular physiology than previously comprehended. Given the variety of cellular disruptions caused by this deficiency, it appears that certain neurons may be more resilient than others. Identifying which altered physiologi- cal processes most significantly contribute to the progression of HD will be imperative for the development of effective therapeutic in- terventions. As current therapeutic strategies under development aim to reduce Htt levels, it is also essential to ascertain the degree to which cells can tolerate a reduction in normal Htt expression. In the field of human disease research, utiliz- ing human subjects is considered the benchmark for validating experimental find- ings related to disease pathogenesis. This approach is instrumental in elucidating the mechanisms underlying disease onset and in exploring viable treatment modalities for ge- netic disorders. Take HD, for instance, a ge- netic condition precipitated by the incessant elongation of the CAG trinucleotide repeat within the Htt gene. The extent of this repeat sequence is a determinant of the age at which HD symptoms manifest, as the accu- mulation of toxicity from the expanded repeat sequence reaches a critical threshold, insti- gating cellular damage processes that cul- Columbia Undergraduate Science Journal Vol. 17, 2023 Datta 26 minate in neuronal impairment and the onset of the disease. However, the length of the CAG repeat is not static; it is subject to so- matic expansion influenced by both genetic and environmental factors. This variability leads to differential susceptibility, damage, and toxicity across various cell types, result- ing in diverse phenotypic expressions among individuals. Thus, the DNA repair mecha- nisms that govern the length of the CAG re- peat are pivotal targets for therapeutic inter- ventions aimed at delaying or averting the onset of HD and similar trinucleotide repeat disorders. Nonetheless, these DNA repair mechanisms are modulated by a plethora of genes that serve as modifiers of HD onset, complicating the prediction of disease trajec- tory for individual patients. Furthermore, these modifier genes may influence not only DNA repair pathways but also other pro- cesses that initiate cellular damage and tox- icity in HD. Another dimension of HD that remains elusive is the normal function of the Htt protein, which is implicated in synaptic vesicle trafficking and endosomal signaling— processes that are crucial for neuronal de- velopment and functionality. The precise mechanisms by which Htt facilitates these synaptic functions, and how they are dis- rupted by the mutant form of Htt in HD- afflicted neurons, are areas that warrant fur- ther investigation. A more thorough charac- terization of the normal roles of Htt could un- veil new therapeutic avenues and foster a more holistic understanding of HD. . 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