1,808 results match your criteria mutant htt

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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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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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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Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease.

Cell Rep 2021 Jul;36(1):109308

Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen 2200, Denmark; Neuroscience Center, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark. Electronic address:

Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT. 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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Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter.

Int J Mol Sci 2021 Jun 30;22(13). Epub 2021 Jun 30.

Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany.

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. 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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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

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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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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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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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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Differential development and electrophysiological activity in cultured cortical neurons from the mouse and cynomolgus monkey.

Neural Regen Res 2021 Dec;16(12):2446-2452

Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration; Key Laboratory of CNS Regeneration, Ministry of Education, Jinan University, Guangzhou, Guangdong Province, China.

In vitro cultures of primary cortical neurons are widely used to investigate neuronal function. However, it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons, and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions. Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods, our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice. Read More

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December 2021

Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species.

J Neuroinflammation 2021 Apr 19;18(1):94. Epub 2021 Apr 19.

Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK.

Background: Neuroinflammation may contribute to the pathogenesis of Huntington's disease, given evidence of activated microglia and elevated levels of inflammatory molecules in disease gene carriers, even those many years from symptom onset. We have shown previously that monocytes from Huntington's disease patients are hyper-reactive to stimulation in a manner dependent on their autonomous expression of the disease-causing mutant HTT protein. To date, however, whether human microglia are similarly hyper-responsive in a cell-autonomous manner has not been determined. Read More

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Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.

Acta Neuropathol Commun 2021 04 14;9(1):70. Epub 2021 Apr 14.

Institute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, UK.

Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. Read More

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Huntingtin-mediated axonal transport requires arginine methylation by PRMT6.

Cell Rep 2021 Apr;35(2):108980

Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy. Electronic address:

The huntingtin (HTT) protein transports various organelles, including vesicles containing neurotrophic factors, from embryonic development throughout life. To better understand how HTT mediates axonal transport and why this function is disrupted in Huntington's disease (HD), we study vesicle-associated HTT and find that it is dimethylated at a highly conserved arginine residue (R118) by the protein arginine methyltransferase 6 (PRMT6). Without R118 methylation, HTT associates less with vesicles, anterograde trafficking is diminished, and neuronal death ensues-very similar to what occurs in HD. 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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In Silico Analysis of Huntingtin Homologs in Lower Eukaryotes.

Int J Mol Sci 2021 Mar 22;22(6). Epub 2021 Mar 22.

Department of Sciences, Roma Tre University, 00146 Rome, Italy.

Huntington's disease is a rare neurodegenerative and autosomal dominant disorder. HD is caused by a mutation in the gene coding for huntingtin (Htt). The result is the production of a mutant Htt with an abnormally long polyglutamine repeat that leads to pathological Htt aggregates. Read More

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The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.

Neurotherapeutics 2021 Apr 1. Epub 2021 Apr 1.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Read More

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Deciphering the key mechanisms leading to alteration of lipid metabolism in Drosophila model of Huntington's disease.

Biochim Biophys Acta Mol Basis Dis 2021 Jul 17;1867(7):166127. Epub 2021 Mar 17.

Department of Zoology, University of Delhi, Delhi 110007, India. Electronic address:

Huntington's disease (HD) is an inherited, progressively debilitating disorder marked by prominent degeneration in striatal and cortical brain regions. HD is caused by (CAG) repeat expansion in huntingtin (HTT) gene that translates into a mutant form of the ubiquitously present Huntingtin (HTT) protein. Extensive metabolic dysfunction coexisting with overt neuropathies has been evidenced in clinical and experimental settings of HD. 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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designing of putative peptides for targeting pathological protein Htt in Huntington's disease.

Heliyon 2021 Feb 12;7(2):e06088. Epub 2021 Feb 12.

Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi 110042, India.

Huntington's disease is a neurodegenerative disease caused by CAG repeat in the first exon of HTT (Huntingtin) gene, leading to abnormal form of Htt protein containing enlarged polyglutamine strands of variable length that stick together to form aggregates and is toxic to brain causing brain damage. Complete reversal of brain damage is not possible till date but recovery may be possible by peptide therapy. The peptide-based therapy for Huntington's disease includes both poly Q peptide as well as non poly Q peptides like (QBP1)2, p42, Exendin 4, ED11, CaM, BiP, Leuprorelin peptide. Read More

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February 2021

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice.

Acta Neuropathol 2021 04 6;141(4):565-584. Epub 2021 Feb 6.

Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Casanova 143, Barcelona, Catalonia, Spain.

Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Read More

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