542 results match your criteria mhtt

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

Commun Biol 2021 Jul 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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

Demethyleneberberine: A possible treatment for Huntington's disease.

Med Hypotheses 2021 Jun 29;153:110639. Epub 2021 Jun 29.

Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt. Electronic address:

Huntington disease (HD) is a type of neurodegenerative disease that is characterized by presence of multiple repeats (more than 36) of cytosine-adenine-guanine (CAG) trinucleotides and mutated huntingtin (mHtt). This can further lead to oxidative stress, enhancement in level of ROS/RNS, mitochondrial dysfunction and neuroinflammations. Many clinical and preclinical trials have been conducted so far for the effective treatment of HD however, none of the drugs has shown complete relief. Read More

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

BACHD Mice Recapitulate the Striatal Parvalbuminergic Interneuron Loss Found in Huntington's Disease.

Front Neuroanat 2021 24;15:673177. Epub 2021 May 24.

Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics (CNET), University of Alabama at Birmingham, Birmingham, AL, United States.

Huntington's disease (HD) is a dominantly inherited, adult-onset neurodegenerative disease characterized by motor, psychiatric, and cognitive abnormalities. Neurodegeneration is prominently observed in the striatum where GABAergic medium spiny neurons (MSN) are the most affected neuronal population. Interestingly, recent reports of pathological changes in HD patient striatal tissue have identified a significant reduction in the number of parvalbumin-expressing interneurons which becomes more robust in tissues of higher disease grade. Read More

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF
October 2021

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.

Elife 2021 Apr 19;10. Epub 2021 Apr 19.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of expressing human mutant (m) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. Read More

View Article and Full-Text PDF

Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor.

J Neurochem 2021 Jul 28;158(2):467-481. Epub 2021 Apr 28.

The Shmunis School of Biomedicine and Cancer Research, Cell Biology Division, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

The endoplasmic reticulum (ER)-localized Sigma-1 receptor (S1R) is neuroprotective in models of neurodegenerative diseases, among them Huntington disease (HD). Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high-affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. Read More

View Article and Full-Text PDF

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

View Article and Full-Text PDF

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

View Article and Full-Text PDF

The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington's Disease.

Pharmaceuticals (Basel) 2021 Mar 12;14(3). Epub 2021 Mar 12.

Department of Human Genetics, Ruhr University Bochum, Universitaetsstrasse 150, 44801 Bochum, Germany.

Huntington's disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer's and Parkinson's disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Read More

View Article and Full-Text PDF

Adenosine Receptor and Its Downstream Targets, Mod(mdg4) and Hsp70, Work as a Signaling Pathway Modulating Cytotoxic Damage in .

Front Cell Dev Biol 2021 12;9:651367. Epub 2021 Mar 12.

Biology Centre of the Czech Academy of Sciences, Institute of Entomology, Ceske Budejovice, Czechia.

Adenosine (Ado) is an important signaling molecule involved in stress responses. Studies in mammalian models have shown that Ado regulates signaling mechanisms involved in "danger-sensing" and tissue-protection. Yet, little is known about the role of Ado signaling in . Read More

View Article and Full-Text PDF

Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease.

Neurobiol Dis 2021 Jul 19;154:105336. Epub 2021 Mar 19.

The Department of Human Molecular Genetics & Biochemistry Sackler School of Medicine, Tel Aviv University, Israel. Electronic address:

In Huntington's disease (HD), the mutant huntingtin (mHtt) accumulates as toxic aggregates in the striatum tissue, with deleterious effects on motor-coordination and cognitive functions. Reducing the levels of mHtt is therefore a promising therapeutic strategy. We have previously reported that GSK-3 is a negative regulator of the autophagy/lysosome pathway, which is responsible for intracellular degradation, and is critically important for maintaining neuronal vitality. Read More

View Article and Full-Text PDF

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

View Article and Full-Text PDF

Tunneling nanotubes: A novel pharmacological target for neurodegenerative diseases?

Pharmacol Res 2021 Mar 10:105541. 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

View Article and Full-Text PDF