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Huntingtin associated Protein

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https://www.readbyqxmd.com/read/28096245/prion-like-characteristics-of-polyglutamine-containing-proteins
#1
Margaret M P Pearce, Ron R Kopito
Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ) tracts, which is causative of nine inherited neurodegenerative diseases...
January 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28094373/conformational-dynamics-and-self-association-of-intrinsically-disordered-huntingtin-exon-1-in-cells
#2
Steffen Büning, Abhishek Sharma, Shivang Vachharajani, Estella Newcombe, Angelique Ormsby, Mimi Gao, David Gnutt, Tobias Vöpel, Danny M Hatters, Simon Ebbinghaus
Huntington's disease is caused by a CAG trinucleotide expansion mutation in the Huntingtin gene that leads to an artificially long polyglutamine sequence in the Huntingtin protein. A key feature of the disease is the intracellular aggregation of the Huntingtin exon 1 protein (Httex1) into micrometer sized inclusion bodies. The aggregation process of Httex1 has been extensively studied in vitro, however, the crucial early events of nucleation and aggregation in the cell remain elusive. Here, we studied the conformational dynamics and self-association of Httex1 by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation...
January 17, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/27992085/muscle-atrophy-is-associated-with-cervical-spinal-motoneuron-loss-in-bachd-mouse-model-for-huntington-s-disease
#3
Priscila Aparecida Costa Valadão, Bárbara Campos de Aragão, Jéssica Neves Andrade, Matheus Proença S M Gomes, Giselle Foureaux, Julliane Vasconcelos Joviano-Santos, José Carlos Nogueira, Fabíola Mara Ribeiro, Juan Carlos Tapia, Cristina Guatimosim
Involuntary choreiform movements are clinical hallmark of Huntington's disease, an autosomal dominant neurodegenerative disorder caused by an increased number of CAG trinucleotide repeats in the huntingtin gene. Involuntary movements start with an impairment of facial muscles and then affect trunk and limbs muscles. Huntington's disease symptoms are caused by changes in cortex and striatum neurons induced by mutated huntingtin. However little is known about the impact of this abnormal protein in spinal cord motoneurons that control movement...
December 19, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27984179/immunohistochemical-analysis-of-huntingtin-associated-protein-1in-adult-rat-spinal-cord-and-its-regional-relationship-with-androgen-receptor
#4
Md Nabiul Islam, Yukio Takeshita, Akie Yanai, Amami Imagawa, Mir Rubayet Jahan, Greggory Wroblewski, Joe Nemoto, Ryutaro Fujinaga, Koh Shinoda
Huntingtin-associated protein 1 (HAP1) is a neuronal interactor with causatively polyglutamine (polyQ)-expanded huntingtin in Huntington's disease and also associated with pathologically polyQ-expanded androgen receptor (AR) in spinobulbar muscular atrophy (SBMA), being considered as a protective factor against neurodegenerative apoptosis. In normal brains, it is abundantly expressed particularly in the limbic-hypothalamic regions that tend to be spared from neurodegeneration, whereas the areas with little HAP1 expression, including the striatum, thalamus, cerebral neocortex and cerebellum, are targets in several neurodegenerative diseases...
October 28, 2016: Neuroscience
https://www.readbyqxmd.com/read/27973707/moonlighting-chaperone-like-activity-of-the-universal-regulatory-14-3-3-proteins
#5
REVIEW
Nikolai N Sluchanko, Nikolai B Gusev
The ubiquitous eukaryotic 14-3-3 proteins coordinate multiple cellular processes due to their well-known regulatory function that is based on specific recognition of phosphorylated motifs in their partners. In this context, 14-3-3 proteins have, in reports, been called 'chaperones'. Although in the classical meaning this is not fully correct, recent studies have revealed that 14-3-3 can indeed be an integral part of the protein quality control system, as they: (i) display ATP-independent anti-aggregation ('holdase') activity, similar to that of the unrelated small heat shock proteins; (ii) assist in clearing misfolded proteins by directing them to proteasomes or aggresomes; (iii) cooperate with classical chaperones for substrate refolding; and also (iv) are associated with neurodegenerative disorders by affecting aggregation of tau, prion protein, α-synuclein, and huntingtin, etc...
December 14, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27957684/huntingtin-polyq-mutation-impairs-the-17%C3%AE-estradiol-neuroglobin-pathway-devoted-to-neuron-survival
#6
Maria Teresa Nuzzo, Marco Fiocchetti, Pierangela Totta, Mariarosa A B Melone, Antonella Cardinale, Francesca R Fusco, Stefano Gustincich, Francesca Persichetti, Paolo Ascenzi, Maria Marino
Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i...
December 12, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27938392/ulk1-mediated-phosphorylation-of-atg14-promotes-autophagy-and-is-impaired-in-huntington-s-disease-models
#7
Mitchell S Wold, Junghyun Lim, Véronik Lachance, Zhiqiang Deng, Zhenyu Yue
BACKGROUND: Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD)...
December 9, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27913212/vcp-cooperates-with-ubxd1-to-degrade-mitochondrial-outer-membrane-protein-mcl1-in-model-of-huntington-s-disease
#8
Xing Guo, Xin Qi
Proteasome-dependent turnover of mitochondrial outer membrane (OMM)-associated proteins is one of the mechanisms for maintaining proper mitochondrial quality and function. However, the underlying pathways and their implications in human disease are poorly understood. Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by expanded CAG repeats in the N terminal of the huntingtin gene (mutant Huntingtin, mtHtt). In this study, we show an extensive degradation of the OMM protein MCL1 (Myeloid cell leukemia sequence 1) in both HD mouse striatal cells and HD patient fibroblasts...
February 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27892468/somatic-increase-of-cct8-mimics-proteostasis-of-human-pluripotent-stem-cells-and-extends-c-elegans-lifespan
#9
Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, David Vilchez
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27891320/the-association-of-vdac-with-cell-viability-of-pc12-model-of-huntington-s-disease
#10
Andonis Karachitos, Daria Grobys, Klaudia Kulczyńska, Adrian Sobusiak, Hanna Kmita
It is becoming increasingly apparent that mitochondria dysfunction plays an important role in the pathogenesis of Huntington's disease (HD), but the underlying mechanism is still elusive. Thus, there is a still need for further studies concerning the upstream events in the mitochondria dysfunction that could contribute to cell death observed in HD. Taking into account the fundamental role of the voltage-dependent anion-selective channel (VDAC) in mitochondria functioning, it is reasonable to consider the channel as a crucial element in HD etiology...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27857176/glycation-potentiates-neurodegeneration-in-models-of-huntington-s-disease
#11
Hugo Vicente Miranda, Marcos António Gomes, Joana Branco-Santos, Carlo Breda, Diana F Lázaro, Luísa Vaqueiro Lopes, Federico Herrera, Flaviano Giorgini, Tiago Fleming Outeiro
Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models...
November 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27815841/the-ubiquitin-receptor-adrm1-modulates-hap40-induced-proteasome-activity
#12
Zih-Ning Huang, Lu-Shiun Her
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an N-terminal expansion of polyglutamine stretch (polyQ) of huntingtin (Htt) protein. HAP40 is a huntingtin-associated protein with unknown cellular functions. Increased HAP40 expression has been reported in the brain of HD patients and HD mouse model. However, the relationship between the elevation of HAP40 and HD etiology remains elusive. In this study, we demonstrated that overexpression of HAP40 enhanced accumulation of mutant Htt aggregates and caused defects in proteasome function...
November 5, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27739513/fus-tls-acts-as-an-aggregation-dependent-modifier-of-polyglutamine-disease-model-mice
#13
Yoshihiro Kino, Chika Washizu, Masaru Kurosawa, Mizuki Yamada, Hiroshi Doi, Toru Takumi, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, Geoffrey G Hicks, Nobutaka Hattori, Tomomi Shimogori, Nobuyuki Nukina
FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS...
October 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27737633/huntingtin-associated-protein-1-eutherian-adaptation-from-a%C3%A2-trak-like-protein-conserved-gene-promoter-elements-and-localization-in-the-human-intestine
#14
Amanda L Lumsden, Richard L Young, Nektaria Pezos, Damien J Keating
BACKGROUND: Huntingtin-associated Protein 1 (HAP1) is expressed in neurons and endocrine cells, and is critical for postnatal survival in mice. HAP1 shares a conserved "HAP1_N" domain with TRAfficking Kinesin proteins TRAK1 and TRAK2 (vertebrate), Milton (Drosophila) and T27A3.1 (C. elegans). HAP1, TRAK1 and TRAK2 have a degree of common function, particularly regarding intracellular receptor trafficking. However, TRAK1, TRAK2 and Milton (which have a "Milt/TRAK" domain that is absent in human and rodent HAP1) differ in function to HAP1 in that they are mitochondrial transport proteins, while HAP1 has emerging roles in starvation response...
October 13, 2016: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/27721240/targeting-cag-repeat-rnas-reduces-huntington-s-disease-phenotype-independently-of-huntingtin-levels
#15
Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M Teresa Zomeño-Abellán, Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, Eulàlia Martí
Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27717053/coupling-of-d2r-short-but-not-d2r-long-receptor-isoform-to-the-rho-rock-signaling-pathway-renders-striatal-neurons-vulnerable-to-mutant-huntingtin
#16
Beatriz Galan-Rodriguez, Elodie Martin, Emmanuel Brouillet, Nicole Déglon, Sandrine Betuing, Jocelyne Caboche
Huntington's disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin-mediated toxicity...
January 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27714635/mitochondria-associated-membranes-mams-overview-and-its-role-in-parkinson-s-disease
#17
M Rodríguez-Arribas, S M S Yakhine-Diop, J M Bravo-San Pedro, P Gómez-Suaga, R Gómez-Sánchez, G Martínez-Chacón, J M Fuentes, R A González-Polo, M Niso-Santano
Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i...
October 6, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27689619/autophagy-activation-by-transcription-factor-eb-tfeb-in-striatum-of-hdq175-q7-mice
#18
Petr Vodicka, Kathryn Chase, Maria Iuliano, Adelaide Tousley, Dana T Valentine, Ellen Sapp, Kimberly B Kegel-Gleason, Miguel Sena-Esteves, Neil Aronin, Marian DiFiglia
BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels. METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9...
October 1, 2016: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/27639641/energy-defects-in-huntington-s-disease-why-in%C3%A2-vivo-evidence-matters
#19
Géraldine Liot, Julien Valette, Jérémy Pépin, Julien Flament, Emmanuel Brouillet
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt)...
September 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27638888/a-small-molecule-p75ntr-ligand-normalizes-signalling-and-reduces-huntington-s-disease-phenotypes-in-r6-2-and-bachd-mice
#20
Danielle A Simmons, Nadia P Belichenko, Ellen C Ford, Sarah Semaan, Marie Monbureau, Sruti Aiyaswamy, Cameron M Holman, Christina Condon, Mehrdad Shamloo, Stephen M Massa, Frank M Longo
Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75(NTR) signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75(NTR) -: associated deleterious signalling and decreases survival signalling suggesting that p75(NTR) could be a valuable therapeutic target...
September 16, 2016: Human Molecular Genetics
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