scholarly journals Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

2021 ◽  
Vol 15 ◽  
Author(s):  
Hidetoshi Komatsu
Keyword(s):  
Nucleic Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Throughput Screening ◽  
Neurodegenerative Disorder ◽  
Direct Injection ◽  
Cag Repeat ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Small Interfering Rnas

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.

scholarly journals Volumetric MRI-Based Biomarkers in Huntington's Disease: An Evidentiary Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Kirsi M. Kinnunen ◽  
Adam J. Schwarz ◽  
Emily C. Turner ◽  
Dorian Pustina ◽  
Emily C. Gantman ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Neurodegenerative Disorder ◽  
Motor Impairment ◽  
Cag Repeat ◽  
Longitudinal Change ◽  
Cross Sectional ◽  
Brain Volumes ◽  
Basal Ganglia Structures

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

scholarly journals Striatal Circuit Development and Its Alterations in Huntington’s Disease

2020 ◽  
Author(s):  
Margaux Lebouc ◽  
Quentin Richard ◽  
Maurice Garret ◽  
Jérôme Baufreton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Rodent Models ◽  
Network Development ◽  
Cag Repeat Expansion ◽  
Circuit Development

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

scholarly journals Implications of the Orb2 Amyloid Structure in Huntington’s Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6910
Author(s):  
Rubén Hervás ◽  
Alexey G. Murzin ◽  
Kausik Si
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Autosomal Dominant ◽  
Neurodegenerative Disorder ◽  
Structural Data ◽  
Cag Repeat ◽  
Functional Amyloid ◽  
Drosophila Brain ◽  
Structural Insight ◽  
The Brain

Huntington’s disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington’s disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain.

Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

2010 ◽  
Vol 90 (3) ◽  
pp. 905-981 ◽  
Author(s):  
Chiara Zuccato ◽  
Marta Valenza ◽  
Elena Cattaneo
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Primary Source ◽  
Cag Repeat ◽  
Mutant Protein ◽  
Loss Of Function ◽  
Causative Gene

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.

scholarly journals Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

2020 ◽  
Author(s):  
Nikhil Ratna ◽  
Nitish L Kamble ◽  
Sowmya D V ◽  
Meera Purushottam ◽  
Pramod K Pal ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Tertiary Care ◽  
Psychiatric Morbidity ◽  
Cag Repeat ◽  
Duration Of Illness ◽  
Low Middle Income Countries

Abstract BACKGROUND: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n=81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p<0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

Huntington’s Disease

2008 ◽  
Author(s):  
Adam Rosenblatt
Keyword(s):  
Huntington's Disease ◽  
Movement Disorder ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Triplet Repeat Expansion ◽  
Common Time ◽  
The Individual

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and various psychiatric disturbances. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the huntingtin gene of chromosome 4—a mutation that is inherited as an autosomal dominant. When the number of CAG repeats exceeds 39, the individual harboring it goes on to develop HD. The most common time of onset is in the fourth or fifth decade, but the age of onset is inversely correlated with the size of the triplet repeat expansion. In rare instances, persons with very large expansions may have onset in childhood, and those with expansions only just into the abnormal range may have onset late in life. Children of affected fathers, if they receive the abnormal allele, tend to inherit an allele that is even further expanded, and thus usually experience the onset of symptoms at a younger age than their fathers; this phenomenon is known as paternal anticipation. The progression of HD is inexorable and usually leads to death within 15 to 20 years of symptom onset; patients in the final stages have severe dementia and are unable to speak, eat, or purposefully move. Death typically results from the consequences of immobility such as pneumonia or malnutrition. The movement disorder of HD has two major manifestations: involuntary movements (eg, chorea, dystonia) and impairments of voluntary movement (eg, clumsiness, dysarthria, swallowing difficulties, falls, bradykinesia, rigidity). Chorea generally predominates early in the course and is gradually eclipsed by motor impairment as the disease becomes more advanced. In the end stages, patients are rigid and immobile. A variety of medications are used to suppress chorea in HD, including neuroleptics, benzodiazepines, and dopamine-depleting agents such as tetrabenazine, but it remains controversial whether these agents convey functional, as opposed to cosmetic, benefits. HD, like many other neurodegenerative disorders, is associated with a variety of psychiatric problems. Some of these problems such as insomnia or demoralization may be thought of as nonspecific. They have a variety of causes and are associated with many different medical conditions.

The molecular biology of Huntington's disease

2001 ◽  
Vol 31 (1) ◽  
pp. 3-14 ◽  
Author(s):  
L. W. HO ◽  
J. CARMICHAEL ◽  
J. SWARTZ ◽  
A. WYTTENBACH ◽  
J. RANKIN ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Intranuclear Inclusions ◽  
Progressive Dementia ◽  
Cellular Models

Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).Methods. This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.Results. Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.Conclusions. Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.

scholarly journals Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Natalia P. Rocha ◽  
Fabiola M. Ribeiro ◽  
Erin Furr-Stimming ◽  
Antonio L. Teixeira
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Genetic Disorder ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Gene Encoding ◽  
Ultimate Cause ◽  
The Central Nervous System ◽  
Inflammatory Changes

Huntington’s disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

2009 ◽  
Vol 37 (6) ◽  
pp. 1270-1275 ◽  
Author(s):  
Angela Bithell ◽  
Rory Johnson ◽  
Noel J. Buckley
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Target Genes ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Cag Repeat ◽  
Contributory Factor ◽  
Cellular Models

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

scholarly journals Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Teal Jenkins ◽  
Cailin Deiter ◽  
Reed Campbell ◽  
Marley Realing ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Latent Infection ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Large Variability ◽  
Yac128 Mouse

AbstractToxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.

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