Genomes and Genes
Summary: A protein that is highly expressed in the nervous system as well as other tissues; its size and structure vary due to polymorphisms. Expanded CAG TRINUCLEOTIDE REPEATS have been identified in the Huntingtin (HD) Gene of patients with HUNTINGTON DISEASE and are associated with abnormal PROTEIN AGGREGATES. Huntingtin interacts with proteins involved in a variety of gene expression and cellular processes; it is also essential for embryonic development.
- Simard O, Niavarani S, Gaudreault V, Boissonneault G. Torsional stress promotes trinucleotidic expansion in spermatids. Mutat Res. 2017;800-802:1-7 pubmed publisher..The transient increase in torsional stress during spermiogenesis may therefore provide an ideal context for the generation of such secondary DNA structures leading to the paternal anticipation of trinucleotidic diseases. ..
- Coffey S, Bragg R, Minnig S, Ament S, Cantle J, Glickenhaus A, et al. Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington's disease. PLoS ONE. 2017;12:e0175968 pubmed publisher..Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver (64% knockdown), brown adipose (66% knockdown), and white adipose ..
- Shrivastava A, Aperia A, Melki R, Triller A. Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions. Neuron. 2017;95:33-50 pubmed publisher..These processes open up new avenues for therapeutics development targeting the initial interactions of deleterious proteins with the plasma membrane or the subsequent pathological signaling. ..
- Wen J, Scoles D, Facelli J. Structure prediction of polyglutamine disease proteins: comparison of methods. BMC Bioinformatics. 2014;15 Suppl 7:S11 pubmed publisher..Both I-TASSER and Rosetta can be used for structure prediction of proteins with poly-Q repeats. Knowledge of poly-Q structure may significantly contribute to development of therapeutic strategies for poly-Q diseases. ..
- Mestre T, Sampaio C. Huntington Disease: Linking Pathogenesis to the Development of Experimental Therapeutics. Curr Neurol Neurosci Rep. 2017;17:18 pubmed publisher..Huntingtin-lowering therapeutics are eagerly awaited as the first interventions that may be able to change the course of HD in a meaningful way. ..
- Moruno Manchon J, Uzor N, Blasco Conesa M, Mannuru S, Putluri N, Furr Stimming E, et al. Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease. Hum Mol Genet. 2017;26:1305-1317 pubmed publisher..Our results identify a novel regulator of mutant huntingtin-mediated neurotoxicity and provide a new target for developing therapies for HD. ..
- Zheng J, Yang J, Choe Y, Hao X, Cao X, Zhao Q, et al. Role of the ribosomal quality control machinery in nucleocytoplasmic translocation of polyQ-expanded huntingtin exon-1. Biochem Biophys Res Commun. 2017;493:708-717 pubmed publisher..We provide evidence that nuclear accumulation of Httex1-103Q enhances its cytotoxicity, suggesting that the RQC machinery plays an important role in protecting cells against the adverse effects of polyQ expansion proteins. ..
- Bäuerlein F, Saha I, Mishra A, Kalemanov M, Martinez Sanchez A, Klein R, et al. In Situ Architecture and Cellular Interactions of PolyQ Inclusions. Cell. 2017;171:179-187.e10 pubmed publisher..These results suggest that aberrant interactions between fibrils and endomembranes contribute to the deleterious cellular effects of protein aggregation. VIDEO ABSTRACT. ..
- ..Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics. ..
- Kuemmerle S, Gutekunst C, Klein A, Li X, Li S, Beal M, et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol. 1999;46:842-9 pubmed..Rather than a harbinger of neuronal death, mutant huntingtin aggregation may be a cytoprotective mechanism against polyglutamine-induced neurotoxicity. ..
- Schuldenzucker V, Schubert R, Muratori L, Freisfeld F, Rieke L, Matheis T, et al. Behavioral testing of minipigs transgenic for the Huntington gene-A three-year observational study. PLoS ONE. 2017;12:e0185970 pubmed publisher..To test long-term safety, tolerability, and efficacy of novel therapeutic approaches in this model reliable assessments applicable longitudinally for several years are warranted for all phenotypical domains relevant in HD...
- Sciacca G, Cicchetti F. Mutant huntingtin protein expression and blood-spinal cord barrier dysfunction in huntington disease. Ann Neurol. 2017;82:981-994 pubmed publisherThe aim of the study was to assess the distribution, frequency, and specific location of mutant huntingtin protein (mHTT) aggregates-the pathological hallmark of Huntington disease (HD)-within the various compartments of the spinal cord ..
- Dietrich P, Johnson I, Alli S, Dragatsis I. Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis. PLoS Genet. 2017;13:e1006846 pubmed publisher..Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis. ..
- Ross C. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?. Neuron. 1997;19:1147-50 pubmed
- . Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015;162:516-26 pubmed publisher..Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders. ..
- Lee A, Ung H, Sands L, Kikis E. A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles. PLoS ONE. 2017;12:e0173644 pubmed publisher..One such disorder is Huntington's Disease (HD) that is caused by a polyglutamine expansion in the human huntingtin protein (htt)...
- Datson N, González Barriga A, Kourkouta E, Weij R, van de Giessen J, Mulders S, et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS ONE. 2017;12:e0171127 pubmed publisher..Based on these encouraging results, (CUG)7 may thus offer an interesting alternative HTT-lowering strategy for HD. ..
- Tobin A, Signer E. Huntington's disease: the challenge for cell biologists. Trends Cell Biol. 2000;10:531-6 pubmed..We suggest that the initial stages of HD result from dysfunction rather than death, and we consider the potential discovery of compounds that might interfere with early pathogenic events. ..
- Nikan M, Osborn M, Coles A, Biscans A, Godinho B, Haraszti R, et al. Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain. Bioconjug Chem. 2017;28:1758-1766 pubmed publisher..Lipophilic ligand conjugation enables siRNA delivery to neural tissues, but rational design of functional, nontoxic siRNA conjugates for CNS delivery remains challenging. ..
- Xu H, An J, Xu B. Distinct cellular toxicity of two mutant huntingtin mRNA variants due to translation regulation. PLoS ONE. 2017;12:e0177610 pubmed publisher..These results indicate that the long HTT 3'UTR suppresses translation. Thus, short-form mutant HTT mRNA will be more efficient in producing toxic protein than its long-form counterpart. ..
- Kloster E, Saft C, Akkad D, Epplen J, Arning L. Association of age at onset in Huntington disease with functional promoter variations in NPY and NPY2R. J Mol Med (Berl). 2014;92:177-84 pubmed..Thus, NPY might act through Y2 receptors to slow down the course of HD, and hence, this peptide could be of interest as a possible therapeutic agent. ..
- Grima J, Daigle J, Arbez N, Cunningham K, Zhang K, Ochaba J, et al. Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron. 2017;94:93-107.e6 pubmed publisher..Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets. ..
- Chen J, VanEtten D, Fountain M, Yildirim I, Disney M. Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1. Biochemistry. 2017;56:3463-3474 pubmed publisher..The results will be useful for understanding the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics. ..
- Byrne L, Rodrigues F, Blennow K, Durr A, Leavitt B, Roos R, et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017;16:601-609 pubmed publisher..Medical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation. ..
- Bassi S, Tripathi T, Monziani A, Di Leva F, Biagioli M. Epigenetics of Huntington's Disease. Adv Exp Med Biol. 2017;978:277-299 pubmed publisher..The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities...
- Shin J, Kim K, Chao M, Atwal R, Gillis T, MacDonald M, et al. Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9. Hum Mol Genet. 2016;25:4566-4576 pubmed publisher..The perfect allele selectivity with broad applicability of our strategy in disorders with diverse disease haplotypes should also support precision medicine through inactivation of many other gain-of-function mutations. ..
- Shin A, Shin B, Shin J, Kim K, Atwal R, Hope J, et al. Novel allele-specific quantification methods reveal no effects of adult onset CAG repeats on HTT mRNA and protein levels. Hum Mol Genet. 2017;26:1258-1267 pubmed publisher..These robust allele-specific assays could prove valuable for monitoring the impact of allele-specific gene silencing strategies currently being explored as therapeutic interventions in HD. ..
- Ban J, Chung J, Lee M, Im W, Kim M. MicroRNA-27a reduces mutant hutingtin aggregation in an in vitro model of Huntington's disease. Biochem Biophys Res Commun. 2017;488:316-321 pubmed publisherHuntington's disease (HD) is a fatal genetic disease caused by abnormal aggregation of mutant huntingtin protein (mHtt). Reduction of mHtt aggregation decreases cell death of the brain and is a promising therapeutic strategy of HD...
- Mao Y, Chen X, Xu M, Fujita K, Motoki K, Sasabe T, et al. Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology. Hum Mol Genet. 2016;25:4749-4770 pubmed publisher..Collectively, we suggest approaches targeting the signalling pathway of TEAD/YAP-transcription-dependent necrosis (TRIAD) could lead to a therapeutic development against HD. ..
- Hong Y, Zhao T, Li X, Li S. Mutant Huntingtin Inhibits Î±B-Crystallin Expression and Impairs Exosome Secretion from Astrocytes. J Neurosci. 2017;37:9550-9563 pubmed publisher..Overexpression of Î±B-crystallin could alleviate the deficient exosome release and neuropathology in HD mice. Our results revealed a new pathological pathway that affects the critical support of glial cells to neurons in the HD brain. ..
- Sapp E, Schwarz C, Chase K, Bhide P, Young A, Penney J, et al. Huntingtin localization in brains of normal and Huntington's disease patients. Ann Neurol. 1997;42:604-12 pubmed..Results suggest that there may be changes in the neuronal expression and transport of wild-type and/or mutant huntingtin at early and late stages of neuronal degeneration in affected areas of the HD brain. ..
- Schut M, Patassini S, Kim E, Bullock J, Waldvogel H, Faull R, et al. Effect of post-mortem delay on N-terminal huntingtin protein fragments in human control and Huntington disease brain lysates. PLoS ONE. 2017;12:e0178556 pubmed publisherHuntington disease is associated with elongation of a CAG repeat in the HTT gene that results in a mutant huntingtin protein. Several studies have implicated N-terminal huntingtin protein fragments in Huntington disease pathogenesis...
- Wild E, Tabrizi S. Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 2017;16:837-847 pubmed publisher..Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area ..