429 results match your criteria mhtt proteins

Huntingtin and the Synapse.

Front Cell Neurosci 2021 15;15:689332. Epub 2021 Jun 15.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin () gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. Read More

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Gene targeting techniques for Huntington's disease.

Ageing Res Rev 2021 Jun 5;70:101385. Epub 2021 Jun 5.

Gemstone Honors Program, University of Maryland, College Park, MD 20742, United States; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, United States. Electronic address:

Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. Read More

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Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.

Autophagy 2021 May 24:1-22. Epub 2021 May 24.

The Buck Institute for Research on Aging, Novato, CA, USA.

Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Read More

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Structural insight into transmissive mutant huntingtin species by correlative light and electron microscopy and cryo-electron tomography.

Biochem Biophys Res Commun 2021 Jun 10;560:99-104. Epub 2021 May 10.

Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. Electronic address:

Aggregates of mutant huntingtin (mHTT) containing an expanded polyglutamine (polyQ) tract are hallmarks of Huntington's Disease (HD). Studies have shown that mHTT can spread between cells, leading to the propagation of misfolded protein pathology. However, the structure of transmissive mHTT species, and the molecular mechanisms underlying their transmission remain unknown. Read More

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Emerging Roles of Exosomes in Huntington's Disease.

Int J Mol Sci 2021 Apr 15;22(8). Epub 2021 Apr 15.

Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Laboratory of Applied Proteome Analyses and Research Center PIGMOD, Rumburska 89, 277 21 Libechov, Czech Republic.

Huntington's disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. Read More

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Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway.

Int J Mol Sci 2021 Apr 9;22(8). Epub 2021 Apr 9.

Unité de Biologie Fonctionnelle et Adaptative (BFA), Université de Paris-CNRS, UMR8251 4 rue Marie Andrée Lagroua Weill Halle, CEDEX 13, 75205 Paris, France.

Huntington's disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although is expressed ubiquitously, most of our knowledge has been obtained on neurons. Read More

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Widespread and sustained target engagement in Huntington's disease minipigs upon intrastriatal microRNA-based gene therapy.

Sci Transl Med 2021 04;13(588)

Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands.

Huntingtin (HTT)-lowering therapies hold promise to slow down neurodegeneration in Huntington's disease (HD). Here, we assessed the translatability and long-term durability of recombinant adeno-associated viral vector serotype 5 expressing a microRNA targeting human (rAAV5-miHTT) administered by magnetic resonance imaging-guided convention-enhanced delivery in transgenic HD minipigs. rAAV5-miHTT (1. Read More

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Tunneling nanotubes: A novel pharmacological target for neurodegenerative diseases?

Pharmacol Res 2021 Aug 10;170:105541. Epub 2021 Mar 10.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica& Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

Diversiform ways of intercellular communication are vital links in maintaining homeostasis and disseminating physiological states. Among intercellular bridges, tunneling nanotubes (TNTs) discovered in 2004 were recognized as potential pharmacology targets related to the pathogenesis of common or infrequent neurodegenerative disorders. The neurotoxic aggregates in neurodegenerative diseases including scrapie prion protein (PrPSc), mutant tau protein, amyloid-beta (Aβ) protein, alpha-synuclein (α-syn) as well as mutant Huntington (mHTT) protein could promote TNT formation via certain physiological mechanisms, in turn, mediating the intercellular transmission of neurotoxicity. Read More

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Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.

Nat Commun 2021 03 5;12(1):1461. Epub 2021 Mar 5.

The Scripps Research Institute, Department of Neuroscience, Jupiter, FL, USA.

The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. Depletion of mHtt enhances protein synthesis and increases the speed of ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro. Read More

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Proteolysis targeting chimera technology: a novel strategy for treating diseases of the central nervous system.

Neural Regen Res 2021 Oct;16(10):1944-1949

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China.

Neurological diseases such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease are among the intractable diseases for which appropriate drugs and treatments are lacking. Proteolysis targeting chimera (PROTAC) technology is a novel strategy to solve this problem. PROTAC technology uses the ubiquitin-protease system to eliminate mutated, denatured, and harmful proteins in cells. Read More

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October 2021

Discovery of the First Druggable GPR52 Antagonist to Treat Huntington's Disease.

J Med Chem 2021 01 14;64(2):938-940. Epub 2021 Jan 14.

Medical Affairs, Kyowa Pharmaceutical Industry Co., Ltd., Osaka 530-0005, Japan.

GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum, and represents an emerging therapeutic target for Huntington's disease (HD), an incurable monogenic neurodegenerative disorder caused by the mutation of the huntingtin (mHTT) gene. This Viewpoint discusses the discovery, published in this journal, that a highly potent and specific GPR52 antagonist was identified through high-throughput screening and structure-activity relationship study, which diminishes not only mHTT protein levels, but also ameliorates HD-like phenotypes in the animal disease models. This strategy offers intriguing promise as a surprising approach for HD therapy, where nucleic acid medicine approaches such as small interference RNAs have been the main focus and encounter obstacles such as delivery efficiency. Read More

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January 2021

Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model.

Sci Rep 2021 01 8;11(1):96. Epub 2021 Jan 8.

Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India.

Maintenance of cellular proteostasis is vital for post-mitotic cells like neurons to sustain normal physiological function and homeostasis, defects in which are established hallmarks of several age-related conditions like AD, PD, HD, and ALS. The Spatio-temporal accumulation of aggregated proteins in the form of inclusion bodies/plaques is one of the major characteristics of many neurodegenerative diseases, including Huntington's disease (HD). Toxic accumulation of HUNTINGTIN (HTT) aggregates in neurons bring about the aberrant phenotypes of HD, including severe motor dysfunction, dementia, and cognitive impairment at the organismal level, in an age-dependent manner. Read More

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January 2021

Analysis of mutant and total huntingtin expression in Huntington's disease murine models.

Sci Rep 2020 12 17;10(1):22137. Epub 2020 Dec 17.

Department of Translational Biology, IRBM S.p.A., via Pontina Km 30, 600, Pomezia, Rome, Italy.

Huntington's disease (HD) is a monogenetic neurodegenerative disorder that is caused by the expansion of a polyglutamine region within the huntingtin (HTT) protein, but there is still an incomplete understanding of the molecular mechanisms that drive pathology. Expression of the mutant form of HTT is a key aspect of diseased tissues, and the most promising therapeutic approaches aim to lower expanded HTT levels. Consequently, the investigation of HTT expression in time and in multiple tissues, with assays that accurately quantify expanded and non-expanded HTT, are required to delineate HTT homeostasis and to best design and interpret pharmacodynamic readouts for HTT lowering therapeutics. Read More

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December 2020

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

Sci Transl Med 2020 12;12(574)

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Read More

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December 2020

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.

J Neurosci 2021 01 11;41(4):780-796. Epub 2020 Dec 11.

Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32828

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin () gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. Read More

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January 2021

LAMP2A-mediated autophagy involved in Huntington's disease progression.

Biochem Biophys Res Commun 2021 01 22;534:561-567. Epub 2020 Nov 22.

Department of Life Science, Kyonggi University, Suwon, South Korea. Electronic address:

Huntington's disease (HD) is caused by a mutant huntingtin (mHtt) protein that contains abnormally extended polyglutamine (polyQ) repeats. The process of autophagy has been implicated in clearing mHtt aggregates, and microRNAs (miRNAs) have been reported as new players to regulate autophagy. However, the autophagy-associated target molecule of let7b miRNA remains unclear in HD. Read More

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January 2021

Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.

Sci Rep 2020 11 20;10(1):20295. Epub 2020 Nov 20.

Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.

In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. Read More

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November 2020

GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes.

J Med Chem 2021 01 13;64(2):941-957. Epub 2020 Nov 13.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp- with an IC value of 0. Read More

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January 2021

Cell Replacement Therapy for Huntington's Disease.

Adv Exp Med Biol 2020 ;1266:57-69

Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, SMS, FMHS, University of Auckland, Auckland, New Zealand.

Huntington's disease (HD) is an inherited neurodegenerative disorder which is characterised by a triad of highly debilitating motor, cognitive, and psychiatric symptoms. While cell death occurs in many brain regions, GABAergic medium spiny neurons (MSNs) in the striatum experience preferential and extensive degeneration. Unlike most neurodegenerative disorders, HD is caused by a single genetic mutation resulting in a CAG repeat expansion and the production of a mutant Huntingtin protein (mHTT). Read More

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January 2021

Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington's disease cell models.

Sci Rep 2020 09 23;10(1):15511. Epub 2020 Sep 23.

Department of Cell Biology and Neuroscience, Rutgers State University of New Jersey, Nelson Biology Laboratory, 604 Allison Road, Piscataway, NJ, 08854, USA.

Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington's disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103Q-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. Read More

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September 2020

Neural stem cells derived from the developing forebrain of YAC128 mice exhibit pathological features of Huntington's disease.

Cell Prolif 2020 Oct 31;53(10):e12893. Epub 2020 Aug 31.

Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Korea.

Objectives: Huntington's disease (HD) is a devastating neurodegenerative disease caused by polyglutamine (polyQ) expansion in the huntingtin (HTT) gene. Mutant huntingtin (mHTT) is the main cause of HD and is associated with impaired mitochondrial dynamics, ubiquitin-proteasome system and autophagy, as well as tauopathy. In this study, we aimed to establish a new neural stem cell line for HD studies. Read More

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October 2020

Mutant huntingtin does not cross the mitochondrial outer membrane.

Hum Mol Genet 2020 10;29(17):2962-2975

Department of Pharmacology and Toxicology.

Mutant huntingtin (mHTT) is associated with mitochondria, but the exact mitochondrial location of mHTT has not been definitively established. Recently, it was reported that mHTT is present in the intermembrane space and inhibits mitochondrial protein import by interacting with TIM23, a major component of mitochondrial protein import machinery, but evidence for functional ramifications were not provided. We assessed mHTT location using synaptic and nonsynaptic mitochondria isolated from brains of YAC128 mice and subjected to alkali treatment or limited trypsin digestion. Read More

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October 2020

N-acetyl-D-glucosamine kinase binds dynein light chain roadblock 1 and promotes protein aggregate clearance.

Cell Death Dis 2020 08 14;11(8):619. Epub 2020 Aug 14.

Dongguk Medical Institute, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea.

Emerging evidence indicates that neurodegenerative diseases (NDs) result from a failure to clear toxic protein aggregates rather than from their generation. We previously showed N-acetylglucosamine kinase (NAGK) promotes dynein functionality and suggested this might promote aggregate removal and effectively address proteinopathies. Here, we report NAGK interacts with dynein light chain roadblock type 1 (DYNLRB1) and efficiently suppresses mutant huntingtin (mHtt) (Q74) and α-synuclein (α-syn) A53T aggregation in mouse brain cells. Read More

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Decreased Myocyte Enhancer Factor 2 Levels in the Hippocampus of Huntington's Disease Mice Are Related to Cognitive Dysfunction.

Mol Neurobiol 2020 Nov 5;57(11):4549-4562. Epub 2020 Aug 5.

New Therapeutic Targets Group, Department of Medical Science, Faculty of Medicine, University of Girona, 17003, Girona, Spain.

People suffering from Huntington's disease (HD) present cognitive deficits. Hippocampal dysfunction has been involved in the HD learning and memory impairment, but proteins leading this dysregulation are not fully characterized. Here, we studied the contribution of the family of transcription factors myocyte enhancer factor 2 (MEF2) to the HD cognitive deficits. Read More

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November 2020

Nascent mutant Huntingtin exon 1 chains do not stall on ribosomes during translation but aggregates do recruit machinery involved in ribosome quality control and RNA.

PLoS One 2020 31;15(7):e0233583. Epub 2020 Jul 31.

Department of Biochemistry and Molecular Biology; and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, VIC, Australia.

Mutations that cause Huntington's Disease involve a polyglutamine (polyQ) sequence expansion beyond 35 repeats in exon 1 of Huntingtin. Intracellular inclusion bodies of mutant Huntingtin protein are a key feature of Huntington's disease brain pathology. We previously showed that in cell culture the formation of inclusions involved the assembly of disordered structures of mHtt exon 1 fragments (Httex1) and they were enriched with translational machinery when first formed. Read More

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September 2020

Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease.

Cell Death Dis 2020 07 30;11(7):569. Epub 2020 Jul 30.

Department of Biomedicine, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain.

RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Read More

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Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation.

Neuron 2020 09 17;107(5):891-908.e8. Epub 2020 Jul 17.

Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Read More

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September 2020

Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects.

Proc Natl Acad Sci U S A 2020 08 16;117(31):18661-18669. Epub 2020 Jul 16.

The Rappaport Faculty of Medicine and Research Institute, 3109601 Haifa, Israel;

Huntington's disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a cytosine-adenine-guanine triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine stretch in the protein product which becomes aggregation prone. The mutant Htt (mHtt) aggregates are associated with components of the ubiquitin-proteasome system, suggesting that mHtt is marked for proteasomal degradation and that, for reasons still debated, are not properly degraded. Read More

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Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

J Med Chem 2020 08 30;63(15):8608-8633. Epub 2020 Jul 30.

Albany Molecular Research, Inc., 1001 Main St., Buffalo, New York 14203, United States.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound , which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. Read More

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Therapeutic strategies for Huntington's disease.

Curr Opin Neurol 2020 08;33(4):508-518

University College London (UCL), Huntington's Disease Centre.

Purpose Of Review: Huntington's disease is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, and current therapies focus on symptomatic treatment. This review explores therapeutic approaches that directly target the pathogenic mutation, disrupt HTT mRNA or its translation.

Recent Findings: Zinc-finger transcription repressors and CRISPR-Cas9 therapies target HTT DNA, thereby preventing all downstream pathogenic mechanisms. Read More

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