Therapeutic Advances for Huntington’s Disease

Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

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Mitochondrial Dysfunction in Huntington’s disease: Pathogenesis and Therapeutic Opportunities

Current Drug Targets ◽

10.2174/1389450122666210224105945 ◽

2021 ◽

Vol 22 ◽

Author(s):

Aditi Sharma ◽

Tapan Behl ◽

Lalit Sharma ◽

Lotfi Aelya ◽

Simona Bungau

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Symptoms ◽

Neuronal Degeneration ◽

Cag Repeats ◽

Ros Generation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Psychiatric Disturbances ◽

Apoptotic Pathways

: Huntington’s disease (HD) is prototypical neurodegenerative disease, preferentially disrupts the neurons of striatum and cor-tex. Progressive motor dysfunctions, psychiatric disturbances, behavioural impairments and cognitive decline are the clinical symptoms of HD progression. The disease occurs due to, expanded CAG repeats in exon 1 of huntingtin protein (mHtt) causing its aggregation. Multiple cellular and molecular pathways are involved in the HD pathology. Mitochondria as vital organelles has an important role in most of the neurodegenerative diseases like HD. Over the years, the role of mitochondria in neurons are highly diverged, it not only contribute as cell power source, but as a dynamic organelles it fragments and then fuse to attain a maximal bioenergetics performance, regulate intracellular calcium homeostasis, reactive oxygen species (ROS) generation, antioxidant activity and involved in apoptotic pathways. Indeed, these events are seen to be affected in HD, resulting in neuronal dysfunction in pre-symptomatic stages. mHtt causes critical transcriptional abnormality by altering the expression of a master co-regulator, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), leading to increased susceptibility to oxidative stress and neuronal degeneration. Moreover, mHtt influences multiple cellular signal-ling events which ends with mitochondrial biogenesis. Here, we resume recent findings that pose mitochondria as an im-portant regulatory organelle in HD and how mHtt affects mitochondrial function, trafficking and homeostasis and makes neurons prone to degeneration. In addition, we also uncover the mitochondrial based potential targets and therapeutic ap-proaches with imminent or currently ongoing clinical trials.

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Electrophysiological and Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice

Journal of Neurophysiology ◽

10.1152/jn.2001.86.6.2667 ◽

2001 ◽

Vol 86 (6) ◽

pp. 2667-2677 ◽

Cited By ~ 209

Author(s):

Gloria J. Klapstein ◽

Robin S. Fisher ◽

Hadi Zanjani ◽

Carlos Cepeda ◽

Eve S. Jokel ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Action Potentials ◽

Morphological Changes ◽

Brain Slices ◽

Cag Repeats ◽

Membrane Properties ◽

Striatal Neurons ◽

Spiny Neurons ◽

Active Membrane

We examined passive and active membrane properties and synaptic responses of medium-sized spiny striatal neurons in brain slices from presymptomatic (∼40 days of age) and symptomatic (∼90 days of age) R6/2 transgenics, a mouse model of Huntington's disease (HD) and their age-matched wild-type (WT) controls. This transgenic expresses exon 1 of the human HD gene with ∼150 CAG repeats and displays a progressive behavioral phenotype associated with numerous neuronal alterations. Intracellular recordings were obtained using standard techniques from R6/2 and age-matched WT mice. Few electrophysiological changes occurred in striatal neurons from presymptomatic R6/2 mice. The changes in this age group were increased neuronal input resistance and lower stimulus intensity to evoke action potentials (rheobase). Symptomatic R6/2 mice exhibited numerous electrophysiological alterations, including depolarized resting membrane potentials, increased input resistances, decreased membrane time constants, and alterations in action potentials. Increased stimulus intensities were required to evoke excitatory postsynaptic potentials (EPSPs) in neurons from symptomatic R6/2 transgenics. These EPSPs had slower rise times and did not decay back to baseline by 45 ms, suggesting a more prominent component mediated by activation of N-methyl-d-aspartate receptors. Neurons from both pre- and symptomatic R6/2 mice exhibited reduced paired-pulse facilitation. Data from biocytin-filled or Golgi-impregnated neurons demonstrated decreased dendritic spine densities, smaller diameters of dendritic shafts, and smaller dendritic fields in symptomatic R6/2 mice. Taken together, these findings indicate that passive and active membrane and synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic. These physiological and morphological alterations will affect communication in the basal ganglia circuitry. Furthermore, they suggest areas to target for pharmacotherapies to alleviate and reduce the symptoms of HD.

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Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212499 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12499

Author(s):

Chaebin Kim ◽

Ali Yousefian-Jazi ◽

Seung-Hye Choi ◽

Inyoung Chang ◽

Junghee Lee ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Involuntary Movement ◽

Therapeutic Approaches ◽

Exon 1 ◽

Human Chromosome 4 ◽

The Brain

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

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The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.761714 ◽

2021 ◽

Vol 12 ◽

Author(s):

Annika Heinz ◽

Judith Schilling ◽

Willeke van Roon-Mom ◽

Sybille Krauß

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Protein A ◽

Cag Repeat ◽

Cag Repeats ◽

Progressive Movement ◽

Promising Therapeutic Target ◽

Promising Therapeutic Approach ◽

Exon 1 ◽

Polyglutamine Protein

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

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The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.616886 ◽

2021 ◽

Vol 14 ◽

Author(s):

Katharina Hecklau ◽

Susanne Mueller ◽

Stefan Paul Koch ◽

Mustafa Hussain Mehkary ◽

Busra Kilic ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Selective Inhibition ◽

Skill Learning ◽

Disease Stage ◽

Therapeutic Effects ◽

Modest Improvement ◽

Symptomatic Disease ◽

Histone Deacetylase 1 ◽

Transcriptional Dysregulation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

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A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

Academic Forensic Pathology ◽

10.23907/2017.016 ◽

2017 ◽

Vol 7 (1) ◽

pp. 136-144

Author(s):

Catherine R. Miller ◽

Nobby C. Mambo ◽

Jianli Dong ◽

Gerald A. Campbell

Keyword(s):

Genetic Testing ◽

Huntington Disease ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Case Reports ◽

Neuronal Loss ◽

Cag Repeat ◽

Cag Repeats ◽

Psychiatric Disturbances ◽

Personality Changes

Huntington disease (HD) is a neurodegenerative disorder with a worldwide prevalence of four to ten per 100 000. It is characterized by choreiform movements, behavioral/psychiatric disturbances, and eventual cognitive decline. Symptoms usually present between 30 and 50 years of age and the diagnosis is based on the combination of clinical symptoms, family history, and genetic testing. A variation of HD, juvenile Huntington disease (JHD), presents earlier, with more severe symptoms and with a worse prognosis. Symptoms are different in JHD, with personality changes and learning difficulties being the predominant presenting features. Seizures are common in JHD, and chorea is uncommon; movement disorders at presentation of JHD are predominantly nonchoreiform. The inheritance pattern for both HD and JHD is autosomal dominant and the disease is caused by an elongation of the CAG repeat in the huntingtin gene. There are many published case reports of Huntington disease that were confirmed at autopsy, but to our knowledge, there are no reports in the literature where the diagnosis of Huntington disease was first made at autopsy. We present a case of a 28-year-old African-American male who was in a state of neglect due to a lifetime of abuse, cognitive difficulties, and seizures, whose cause of death was pneumonia. The gross autopsy findings included bilateral caudate nucleus atrophy and lateral ventricular dilation. Microscopically, severe bilateral neuronal loss and gliosis of the caudate and putamen nuclei were seen. Genetic testing for the number of CAG repeats confirmed the diagnosis and was consistent with JHD.

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Recent Overview of the Use of iPSCs Huntington’s Disease Modeling and Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21062239 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2239 ◽

Cited By ~ 6

Author(s):

Maria Csobonyeiova ◽

Stefan Polak ◽

Lubos Danisovic

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Modeling ◽

Cell Types ◽

Cag Repeats ◽

Neural Cells ◽

Behavioral Impairment ◽

Cell Based Therapy

Huntington’s disease (HD) is an inherited, autosomal dominant, degenerative disease characterized by involuntary movements, cognitive decline, and behavioral impairment ending in death. HD is caused by an expansion in the number of CAG repeats in the huntingtin gene on chromosome 4. To date, no effective therapy for preventing the onset or progression of the disease has been found, and many symptoms do not respond to pharmacologic treatment. However, recent results of pre-clinical trials suggest a beneficial effect of stem-cell-based therapy. Induced pluripotent stem cells (iPSCs) represent an unlimited cell source and are the most suitable among the various types of autologous stem cells due to their patient specificity and ability to differentiate into a variety of cell types both in vitro and in vivo. Furthermore, the cultivation of iPSC-derived neural cells offers the possibility of studying the etiopathology of neurodegenerative diseases, such as HD. Moreover, differentiated neural cells can organize into three-dimensional (3D) organoids, mimicking the complex architecture of the brain. In this article, we present a comprehensive review of recent HD models, the methods for differentiating HD–iPSCs into the desired neural cell types, and the progress in gene editing techniques leading toward stem-cell-based therapy.

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Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases

Pharmacological Research ◽

10.1016/j.phrs.2015.08.002 ◽

2015 ◽

Vol 100 ◽

pp. 157-169 ◽

Cited By ~ 24

Author(s):

Sorabh Sharma ◽

Rajeev Taliyan

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Histone Deacetylases ◽

Transcriptional Dysregulation

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Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-200413 ◽

2020 ◽

Vol 9 (4) ◽

pp. 335-344

Author(s):

Marcus P.J. van Diemen ◽

Ellen P. Hart ◽

Pieter W. Hameeteman ◽

Emma M. Coppen ◽

Jessica Y. Winder ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mitochondrial Function ◽

Rating Scale ◽

Pearson Correlation ◽

Cag Repeats ◽

Resonance Spectroscopy ◽

Motor Score ◽

Energetic State ◽

Disease Modifying

Background: Huntington’s disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. Objective: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. Methods: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. Results: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = –0.45 and –0.48), which increased in a subgroup with the largest number of CAG repeats. Discussion: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.

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