2,420 results match your criteria mutant huntingtin

Mutant Huntingtin Impairs Pancreatic β-cells by Recruiting IRS-2 and Disturbing the PI3K/AKT/FoxO1 Signaling Pathway in Huntington's Disease.

J Mol Neurosci 2021 Jul 31. Epub 2021 Jul 31.

Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. of China.

Patients with Huntington's disease (HD) have an increased incidence of diabetes. However, the molecular mechanisms of pancreatic β-cell dysfunction have not been entirely clarified. Revealing the pathogenesis of diabetes can provide a novel understanding of the onset and progression of HD, as well as potential clues for the development of new therapeutics. Read More

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J Pharmacol Exp Ther 2021 Jul 30. Epub 2021 Jul 30.

Department of Cellular and Molecular Medicine, University of Ottawa, Canada

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease that leads to progressive motor impairment with no available disease-modifying treatments. Current evidence indicates that exacerbated postsynaptic glutamate signaling in the striatum plays a key role in the pathophysiology of HD. However, it remains unclear whether reducing glutamate release can be an effective approach to slow the progression of HD. Read More

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Neuroprotective effects of rutin on ASH neurons in model of Huntington's disease.

Nutr Neurosci 2021 Jul 26:1-14. Epub 2021 Jul 26.

Centro de Ciências Naturais e Exatas, Departamento de Bioquímica e Biologia Molecular, Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, Brazil.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disease. It occurs due to a mutated huntingtin gene that contains an abnormal expansion of cytosine-adenine-guanine repeats, leading to a variable-length N-terminal polyglutamine (polyQ) chain. The mutation confers toxic functions to mutant huntingtin protein, causing neurodegeneration. Read More

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SQSTM1/p62 droplet -mediated autophagosome formation:insights into Huntington disease.

Autophagy 2021 Jul 19:1-4. Epub 2021 Jul 19.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.

Huntington disease (HD) manifests a unique macroautophagy/autophagy defect: the presense of cytosolic autophagosomes without substrates or so-called "empty" autophagosomes. It was proposed that mutant HTT (huntingtin; mHTT) disrupts cargo recognition by the selective autophagy receptor SQSTM1/p62 thus leading to the failure of cargo sequestration by phagophores, the precursors to autophagosomes. Here we looked at recent discoveries that liquid-like SQSTM1 droplets can serve as platforms for autophagosome formation, and discussed possible alternative mechanisms for "empty" autophagosome formation in HD inspired by these findings. Read More

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Hypothalamic pathology in Huntington disease.

Handb Clin Neurol 2021 ;182:245-255

Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany.

Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. Read More

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Accumulation of Endogenous Mutant Huntingtin in Astrocytes Exacerbates Neuropathology of Huntington Disease in Mice.

Mol Neurobiol 2021 Jul 12. Epub 2021 Jul 12.

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.

Selective neuronal accumulation of misfolded proteins is a key step toward neurodegeneration in a wide range of neurodegenerative diseases, including Huntington's (HD) diseases. Our recent studies suggest that Hsp70-binding protein 1 (HspBP1), an Hsp70/CHIP inhibitor that reduces protein folding, is highly expressed in neuronal cells and accounts for the accumulation of the HD protein huntingtin (HTT) in neuronal cells. To further determine the role of HspBP1 in regulation of mutant protein accumulation, we investigated whether increasing expression of HspBP1 in glial cells can also induce the accumulation of endogenous mutant HTT in glial cells and yield non-cell-autonomous toxic effects. Read More

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Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice.

Front Neurosci 2021 22;15:682172. Epub 2021 Jun 22.

Neuroproteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

The deposition of mutant huntingtin (mHTT) protein aggregates in neurons of patients is a pathological hallmark of Huntington's disease (HD). Previous investigations in cell-free and cell-based disease models showed mHTT exon-1 (mHTTex1) fragments with pathogenic polyglutamine (polyQ) tracts (>40 glutamines) to self-assemble into highly stable, β-sheet-rich protein aggregates with a fibrillar morphology. HD knock-in mouse models have not been extensively studied with regard to mHTT aggregation. Read More

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Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates.

Commun Biol 2021 07 8;4(1):849. Epub 2021 Jul 8.

Department of Bioengineering and James H. Clark Center, Stanford University, Stanford, CA, USA.

Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of filamentous mHTT inclusions in the brain (hallmarks of HD implicated in neurotoxicity) remain elusive. Using cryo-electron tomography and subtomogram averaging, here we show that mHTT exon 1 and polyQ-only aggregates in vitro are structurally heterogenous and filamentous, similar to prior observations with other methods. Read More

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Huntington's Chorea-a Rare Neurodegenerative Autosomal Dominant Disease: Insight into Molecular Genetics, Prognosis and Diagnosis.

Appl Biochem Biotechnol 2021 Aug 7;193(8):2634-2648. Epub 2021 Jul 7.

Department of Biotechnology, University of Engineering and Management, Kolkata, University Area, Plot, Street Number 03, Action Area III, B/5, Newtown, Kolkata, West Bengal, 700156, India.

Huntington's disease is a neurodegenerative autosomal disease results due to expansion of polymorphic CAG repeats in the huntingtin gene. Phosphorylation of the translation initiation factor 4E-BP results in the alteration of the translation control leading to unwanted protein synthesis and neuronal function. Consequences of mutant huntington (mhtt) gene transcription are not well known. Read More

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RNA-seq analysis reveals significant transcriptome changes in huntingtin-null human neuroblastoma cells.

BMC Med Genomics 2021 Jul 2;14(1):176. Epub 2021 Jul 2.

Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA.

Background: Huntingtin (Htt) protein is the product of the gene mutated in Huntington's disease (HD), a fatal, autosomal dominant, neurodegenerative disorder. Normal Htt is essential for early embryogenesis and the development of the central nervous system. However, the role of Htt in adult tissues is less defined. Read More

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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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Cell Reprogramming to Model Huntington's Disease: A Comprehensive Review.

Cells 2021 Jun 22;10(7). Epub 2021 Jun 22.

Centre for Brain Research, Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, School of Medical Science, University of Auckland, Auckland 1023, New Zealand.

Huntington's disease (HD) is a neurodegenerative disorder characterized by the progressive decline of motor, cognitive, and psychiatric functions. HD results from an autosomal dominant mutation that causes a trinucleotide CAG repeat expansion and the production of mutant Huntingtin protein (mHTT). This results in the initial selective and progressive loss of medium spiny neurons (MSNs) in the striatum before progressing to involve the whole brain. Read More

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Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease.

Prog Neurobiol 2021 Jun 21:102110. Epub 2021 Jun 21.

Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea; Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address:

Mitochondrial dysfunction is associated with neuronal damage in Huntington's disease (HD), but the precise mechanism of mitochondria-dependent pathogenesis is not understood yet. Herein, we found that colocalization of XIAP and p53 was prominent in the cytosolic compartments of normal subjects but reduced in HD patients and HD transgenic animal models. Overexpression of mutant Huntingtin (mHTT) reduced XIAP levels and elevated mitochondrial localization of p53 in striatal cells in vitro and in vivo. Read More

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A New Chemoenzymatic Semisynthetic Approach Provides Insight into the Role of Phosphorylation beyond Exon1 of Huntingtin and Reveals N-Terminal Fragment Length-Dependent Distinct Mechanisms of Aggregation.

J Am Chem Soc 2021 Jul 23;143(26):9798-9812. Epub 2021 Jun 23.

Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

Huntington's disease is a neurodegenerative disorder caused by the expansion of a polyglutamine repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Httexon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1 (mHttex1). Read More

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Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex.

J Huntingtons Dis 2021 Jun 12. Epub 2021 Jun 12.

Department of Medical Biology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands.

Background: Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein.

Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington's disease pathology.

Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Read More

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Therapeutic potential of ginsenoside Rg3 and Rf for Huntington's disease.

In Vitro Cell Dev Biol Anim 2021 Jun 14;57(6):641-648. Epub 2021 Jun 14.

Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.

Ginseng is a popular herbal medicine and known to have protective and therapeutic effects in various diseases. Ginsenosides are active gradients representing the diverse pharmacological efficacy of ginseng. Huntington's disease (HD) is incurable genetic disorder associated with mutant huntingtin (mHtt) aggregation in the central nervous system. 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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Reliable Resolution of Full-Length Huntingtin Alleles by Quantitative Immunoblotting.

J Huntingtons Dis 2021 Jun 4. Epub 2021 Jun 4.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.

Background: Therapeutics that lower mutant huntingtin (mHTT) have shown promise in preclinical studies and are in clinical development for the treatment of Huntington's disease (HD). Multiple assays have been developed that either quantify mHTT or total HTT but may not accurately measure levels of wild type HTT (wtHTT) in biological samples.

Objective: To optimize a method that can be used to resolve, quantify and directly compare levels of full length wtHTT and mHTT in HD samples. Read More

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Mitochondrial membranes modify mutant huntingtin aggregation.

Biochim Biophys Acta Biomembr 2021 Oct 2;1863(10):183663. Epub 2021 Jun 2.

The C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, WV 26506, United States; Rockefeller Neurosciences Institutes, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, WV 26505, United States; Department of Neuroscience, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, WV 26505, United States. Electronic address:

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ tracts are prone to aggregate into oligomers and insoluble fibrils. Mutant htt (mhtt) localizes to variety of organelles, including mitochondria. Read More

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October 2021

Random Lasing Detection of Mutant Huntingtin Expression in Cells.

Sensors (Basel) 2021 May 31;21(11). Epub 2021 May 31.

Departamento de Física, Instituto Universitario de Estudios Avanzados en Física Atómica, Molecular y Fotónica (IUdEA), Universidad de La Laguna, 38206 Santa Cruz de Tenerife, Spain.

Huntington's disease (HD) is an autosomal dominant, incurable neurodegenerative disease caused by mutation in the huntingtin gene (). mutation leads to protein misfolding and aggregation, which affect cells' functions and structural features. Because these changes might modify the scattering strength of affected cells, we propose that random lasing (RL) is an appropriate technique for detecting cells that express mutated . Read More

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Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Brain 2021 May 27. Epub 2021 May 27.

Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, when clinical outcomes are used to evaluate the effectiveness of therapy. Read More

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Epigenetic regulation in Huntington's disease.

Neurochem Int 2021 Sep 24;148:105074. Epub 2021 May 24.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA. Electronic address:

Huntington's disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Read More

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September 2021

Dysregulation of long non-coding RNAs and their mechanisms in Huntington's disease.

J Neurosci Res 2021 May 24. Epub 2021 May 24.

Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, P.R. China.

Extensive alterations in gene regulatory networks are a typical characteristic of Huntington's disease (HD); these include alterations in protein-coding genes and poorly understood non-coding RNAs (ncRNAs), which are associated with pathology caused by mutant huntingtin. Long non-coding RNAs (lncRNAs) are an important class of ncRNAs involved in a variety of biological functions, including transcriptional regulation and post-transcriptional modification of many targets, and likely contributed to the pathogenesis of HD. While a number of changes in lncRNAs expression have been observed in HD, little is currently known about their functions. 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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Karyopherin abnormalities in neurodegenerative proteinopathies.

Brain 2021 May 21. Epub 2021 May 21.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London SE5 9RT, UK.

Neurodegenerative proteinopathies are characterised by progressive cell loss that is preceded by the mislocalisation and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, alpha-synuclein, Tar DNA binding protein-43, Fused in sarcoma and mutant Huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalised aggregates that characterise the stages and severity of neurodegenerative diseases. 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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Systemic manifestation and contribution of peripheral tissues to Huntington's disease pathogenesis.

Ageing Res Rev 2021 08 9;69:101358. Epub 2021 May 9.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Electronic address:

Huntington disease (HD) is an autosomal dominant neurodegenerative disease that is caused by expansion of cytosine/adenosine/guanine repeats in the huntingtin (HTT) gene, which leads to a toxic, aggregation-prone, mutant HTT-polyQ protein. Beyond the well-established mechanisms of HD progression in the central nervous system, growing evidence indicates that also peripheral tissues are affected in HD and that systemic signaling originating from peripheral tissues can influence the progression of HD in the brain. Herein, we review the systemic manifestation of HD in peripheral tissues, and the impact of systemic signaling on HD pathogenesis. Read More

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SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes.

Brain 2021 May 11. Epub 2021 May 11.

Department of Biosciences, University of Milan, 20133, Milan, Italy.

Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington's disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway. Read More

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Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington's disease.

Proc Natl Acad Sci U S A 2021 May;118(19)

NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;

Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-sequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. Read More

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