Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

The neurodegenerative disorder Huntington’s disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

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Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Human Molecular Genetics ◽

10.1093/hmg/ddy430 ◽

2019 ◽

Vol 29 (11) ◽

pp. 1757-1771 ◽

Cited By ~ 4

Author(s):

◽

Amanda J Kedaigle ◽

Ernest Fraenkel ◽

Ranjit S Atwal ◽

Min Wu ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Induced Pluripotent Stem Cell ◽

Therapeutic Benefit ◽

Neural Cells ◽

Striatal Neurons ◽

Proteomics Data ◽

Postmortem Human Brain ◽

Atp Levels

Abstract Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington’s disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

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Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.742763 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jenny Lange ◽

Alison Wood-Kaczmar ◽

Aneesa Ali ◽

Sahar Farag ◽

Rhia Ghosh ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Nucleocytoplasmic Transport ◽

Cag Repeat ◽

Nuclear Pore ◽

Neuronal Cultures ◽

Striatal Neurons ◽

Lamin B1 ◽

Gene And Protein Expression

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

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The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Journal of Huntington s Disease ◽

10.3233/jhd-200429 ◽

2021 ◽

Vol 10 (1) ◽

pp. 7-33

Author(s):

Darren G. Monckton

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Human Genetics ◽

Age At Onset ◽

Cag Repeat ◽

Model Systems ◽

Causative Mutation ◽

Inverse Association ◽

Independent Manner ◽

Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.785703 ◽

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.

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Neural Transplantation for Huntington's Disease: Experimental Rationale and Recommendations for Clinical Trials

Cell Transplantation ◽

10.1177/096368979600500222 ◽

1996 ◽

Vol 5 (2) ◽

pp. 339-352 ◽

Cited By ~ 12

Author(s):

Kathleen M. Shannon ◽

Jeffrey H. Kordower

Keyword(s):

Clinical Trials ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Treatment Strategies ◽

Neural Transplantation ◽

Trophic Factors ◽

Trophic Factor ◽

Striatal Neurons ◽

Variable Parameters

Huntington's disease (HD) is a neurodegenerative disorder affecting motor function, personality, and cognition. This paper reviews the experimental data that demonstrate the potential for transplantation of fetal striatum and trophic factor secreting cells to serve as innovative treatment strategies for HD. Transplantation strategies have been effective in replacing lost neurons or preventing the degeneration of neurons destined to die in both rodent and nonhuman primate models of HD. In this regard, a logical series of investigations has proven that grafts of fetal striatum survive, reinnervate the host, and restore function impaired following excitotoxic lesions of the striatum. Furthermore, transplants of cells genetically modified to secrete trophic factors such as nerve growth factor protect striatal neurons from degeneration due to excitotoxicity or mitochondrial dysfunction. Given the disabling and progressive nature of HD, coupled with the absence of any meaningful medical therapy, it is reasonable to consider clinical trials of neural transplantation for this disease. Fetal striatal implants will most likely be the first transplant strategy attempted for HD. This paper describes the variable parameters we believe to be critical for consideration for the design of clinical trials using fetal striatal implants for the treatment of HD.

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

Frontiers in Neurology ◽

10.3389/fneur.2021.712555 ◽

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.

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Striatal Circuit Development and Its Alterations in Huntington’s Disease

10.20944/preprints202005.0488.v1 ◽

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.

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Implications of the Orb2 Amyloid Structure in Huntington’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21186910 ◽

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.

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Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

Physiological Reviews ◽

10.1152/physrev.00041.2009 ◽

2010 ◽

Vol 90 (3) ◽

pp. 905-981 ◽

Cited By ~ 524

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.

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