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Huntingtin disease

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https://www.readbyqxmd.com/read/29775574/forms-and-phases-in-huntingtin-protein-aggregation
#1
Michael Elbaum
Using a combination of fluorescence microscopy and electron tomography, Peskett et al. (2018), in this issue of Molecular Cell, explore the nucleation of amyloid-like filaments from liquid-like condensates of huntingtin protein exon1 with disease-related polyQ extensions.
May 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29765031/comprehensive-epigenetic-landscape-of-rheumatoid-arthritis-fibroblast-like-synoviocytes
#2
Rizi Ai, Teresina Laragione, Deepa Hammaker, David L Boyle, Andre Wildberg, Keisuke Maeshima, Emanuele Palescandolo, Vinod Krishna, David Pocalyko, John W Whitaker, Yuchen Bai, Sunil Nagpal, Kurtis E Bachman, Richard I Ainsworth, Mengchi Wang, Bo Ding, Percio S Gulko, Wei Wang, Gary S Firestein
Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles...
May 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29764935/the-disorderly-conduct-of-hsc70-and-its-interaction-with-the-alzheimer-s-related-tau-protein
#3
Isabelle R Taylor, Atta Ahmad, Taia Wu, Bryce A Nordhues, Anup Bhullar, Jason E Gestwicki, Erik R P Zuiderweg
Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71 KDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein tau, which is linked to Alzheimer's disease...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29754822/a-liquid-to-solid-phase-transition-underlying-pathological-huntingtin-exon1-aggregation
#4
Thomas R Peskett, Frédérique Rau, Jonathan O'Driscoll, Rickie Patani, Alan R Lowe, Helen R Saibil
Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N-terminal exon1 fragments of the protein in intracellular aggregates. We combined electron tomography and quantitative fluorescence microscopy to analyze the structural and material properties of huntingtin exon1 assemblies in mammalian cells, in yeast, and in vitro. We found that huntingtin exon1 proteins can form reversible liquid-like assemblies, a process driven by huntingtin's polyQ tract and proline-rich region...
April 24, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29743609/salivary-levels-of-total-huntingtin-are-elevated-in-huntington-s-disease-patients
#5
Jody Corey-Bloom, Ameera S Haque, Sungmee Park, Ajay S Nathan, Robert W Baker, Elizabeth A Thomas
Patients with Huntington's disease (HD), an autosomal-dominant neurodegenerative disease, show substantial variability in age-of-onset, symptom severity and course of illness, warranting the need for biomarkers to anticipate and monitor these features. The HD gene encodes the disease protein huntingtin (Htt), a potentially useful biomarker for this disease. In the current study, we determined whether total Htt protein (normal plus mutant; "tHtt") could be reliably measured in human saliva, a body fluid that is much more accessible compared to cerebral spinal fluid or even blood, and whether salivary levels of tHtt were clinically meaningful...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29743513/sphingosine-kinase-1-associated-autophagy-differs-between-neurons-and-astrocytes
#6
Jose F Moruno-Manchon, Ndidi-Ese Uzor, Chandrashekar R Ambati, Vivekananda Shetty, Nagireddy Putluri, Chinnaswamy Jagannath, Louise D McCullough, Andrey S Tsvetkov
Autophagy is a degradative pathway for removing aggregated proteins, damaged organelles, and parasites. Evidence indicates that autophagic pathways differ between cell types. In neurons, autophagy plays a homeostatic role, compared to a survival mechanism employed by starving non-neuronal cells. We investigated if sphingosine kinase 1 (SK1)-associated autophagy differs between two symbiotic brain cell types-neurons and astrocytes. SK1 synthesizes sphingosine-1-phosphate, which regulates autophagy in non-neuronal cells and in neurons...
May 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29738460/patient-derived-ipscs-and-ins-shedding-new-light-on-the-cellular-etiology-of-neurodegenerative-diseases
#7
Bor Luen Tang
Induced pluripotent stem cells (iPSCs) and induced neuronal (iN) cells are very much touted in terms of their potential promises in therapeutics. However, from a more fundamental perspective, iPSCs and iNs are invaluable tools for the postnatal generation of specific diseased cell types from patients, which may offer insights into disease etiology that are otherwise unobtainable with available animal or human proxies. There are two good recent examples of such important insights with diseased neurons derived via either the iPSC or iN approaches...
May 8, 2018: Cells
https://www.readbyqxmd.com/read/29722299/the-adjustment-of-%C3%AE-aminobutyric-acid-a-tonic-subunits-in-huntington-s-disease-from-transcription-to-translation-to-synaptic-levels-into-the-neostriatum
#8
REVIEW
Abraham Rosas-Arellano, Argel Estrada-Mondragón, Carola A Mantellero, Carlos Tejeda-Guzmán, Maite A Castro
γ-Aminobutyric acid (GABA), plays a key role in all stages of life, also is considered the main inhibitory neurotransmitter. GABA activates two kind of membrane receptors known as GABAA and GABAB , the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6, β3, δ, or ρ1-3 subunits, they are located at perisynaptic and/or in extrasynaptic regions. The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation...
April 2018: Neural Regeneration Research
https://www.readbyqxmd.com/read/29713895/mutant-huntingtin-causes-a-selective-decrease-in-the-expression-of-synaptic-vesicle-protein-2c
#9
Chaohua Peng, Gaochun Zhu, Xiangqian Liu, He Li
Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt...
April 30, 2018: Neuroscience Bulletin
https://www.readbyqxmd.com/read/29709465/huntington-s-disease-pattern-of-transcriptional-dysregulation-in-the-absence-of-mutant-huntingtin-is-produced-by-knockout-of-neuronal-glt-1
#10
Robert B Laprairie, Geraldine T Petr, Yan Sun, Kathryn D Fischer, Eileen M Denovan-Wright, Paul A Rosenberg
GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5-10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD...
April 27, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29694882/cardiac-mtorc1-dysregulation-impacts-stress-adaptation-and-survival-in-huntington-s-disease
#11
Daniel D Child, John H Lee, Christine J Pascua, Yong Hong Chen, Alejandro Mas Monteys, Beverly L Davidson
Huntington's disease (HD) is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). But in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression...
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29694863/insights-into-the-aggregation-mechanism-of-polyq-proteins-with-different-glutamine-repeat-lengths
#12
Tetyana Yushchenko, Elke Deuerling, Karin Hauser
Polyglutamine (polyQ) diseases, including Huntington's disease, result from the aggregation of an abnormally expanded polyQ repeat in the affected protein. The length of the polyQ repeat is essential for the disease's onset; however, the molecular mechanism of polyQ aggregation is still poorly understood. Controlled conditions and initiation of the aggregation process are prerequisites for the detection of transient intermediate states. We present an attenuated total reflection Fourier-transform infrared spectroscopic approach combined with protein immobilization to study polyQ aggregation dependent on the polyQ length...
April 24, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29688337/stimulation-of-s1pr5-with-a-971432-a-selective-agonist-preserves-blood-brain-barrier-integrity-and-exerts-therapeutic-effect-in-an-animal-model-of-huntington-s-disease
#13
Alba Di Pardo, Salvatore Castaldo, Enrico Amico, Giuseppe Pepe, Federico Marracino, Luca Capocci, Alfredo Giovannelli, Michele Madonna, Jeroen van Bergeijk, Fabio Buttari, Elizabeth van der Kam, Vittorio Maglione
Huntington's disease (HD) is the most common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approaches may open the door to new and more targeted treatments for the disease.In this study, we investigated the therapeutic potential of stimulating Sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2 mice, a widely-used HD animal model...
April 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29684586/targeted-biochemical-profiling-of-brain-from-huntington-s-disease-patients-reveals-novel-metabolic-pathways-of-interest
#14
Stewart F Graham, Xiaobei Pan, Ali Yilmaz, Shirin Macias, Andrew Robinson, David Mann, Brian D Green
Huntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-guanosine-guanine (CAG) repeat in the Huntingtin gene. Herein DI/LC-MS/MS was used to accurately identify and quantify 185 metabolites in post mortem frontal lobe and striatum from HD patients and healthy control cases...
April 20, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29682858/natural-biological-variation-of-white-matter-microstructure-is-accentuated-in-huntington-s-disease
#15
Sarah Gregory, Helen Crawford, Kiran Seunarine, Blair Leavitt, Alexandra Durr, Raymund A C Roos, Rachael I Scahill, Sarah J Tabrizi, Geraint Rees, Douglas Langbehn, Michael Orth
Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG-repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome-wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification...
April 22, 2018: Human Brain Mapping
https://www.readbyqxmd.com/read/29671352/huntington-s-disease-novel-therapeutic-perspectives-hanging-in-the-balance
#16
Ana Saavedra, Gerardo García-Díaz Barriga, Esther Pérez-Navarro, Jordi Alberch
Huntington's disease (HD), an autosomal dominant neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin gene, has long been characterized by the presence of motor symptoms due to the loss of striatal projection neurons. Cognitive dysfunction and neuropsychiatric symptoms are also present and they occur in the absence of cell death in most mouse models, pointing to neuronal dysfunction and abnormal synaptic plasticity as causative mechanisms. Areas covered: Here, we focus on those common mechanisms altered by the presence of mutant huntingtin affecting corticostriatal and hippocampal function as therapeutic targets that could prove beneficial to ameliorate both cognitive and motor function in HD...
April 19, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29643462/environment-dependent-striatal-gene-expression-in-the-bachd-rat-model-for-huntington-disease
#17
Arianna Novati, Thomas Hentrich, Zinah Wassouf, Jonasz J Weber, Libo Yu-Taeger, Nicole Déglon, Huu Phuc Nguyen, Julia M Schulze-Hentrich
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene which results in progressive neurodegeneration in the striatum, cortex, and eventually most brain areas. Despite being a monogenic disorder, environmental factors influence HD characteristics. Both human and mouse studies suggest that mutant HTT (mHTT) leads to gene expression changes that harbor potential to be modulated by the environment. Yet, the underlying mechanisms integrating environmental cues into the gene regulatory program have remained largely unclear...
April 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29627459/tadpole-like-conformations-of-huntingtin-exon-1-are-characterized-by-conformational-heterogeneity-that-persists-regardless-of-polyglutamine-length
#18
Estella A Newcombe, Kiersten M Ruff, Ashish Sethi, Angelique R Ormsby, Yasmin M Ramdzan, Archa Fox, Anthony W Purcell, Paul R Gooley, Rohit V Pappu, Danny M Hatters
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen-deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region...
April 5, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29625255/genetic-enhancement-of-macroautophagy-in-vertebrate-models-of-neurodegenerative-diseases
#19
REVIEW
Patrick Ejlerskov, Avraham Ashkenazi, David C Rubinsztein
Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins which are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such disease...
April 3, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29620999/dose-dependent-lowering-of-mutant-huntingtin-using-antisense-oligonucleotides-in-huntington-disease-patients
#20
Willeke M C van Roon-Mom, Raymund A C Roos, Susanne T de Bot
On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data...
April 2018: Nucleic Acid Therapeutics
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