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Huntingtin associated Protein

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https://www.readbyqxmd.com/read/28453524/peripheral-huntingtin-silencing-does-not-ameliorate-central-signs-of-disease-in-the-b6-httq111-mouse-model-of-huntington-s-disease
#1
Sydney R Coffey, Robert M Bragg, Shawn Minnig, Seth A Ament, Jeffrey P Cantle, Anne Glickenhaus, Daniel Shelnut, José M Carrillo, Dominic D Shuttleworth, Julie-Anne Rodier, Kimihiro Noguchi, C Frank Bennett, Nathan D Price, Holly B Kordasiewicz, Jeffrey B Carroll
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD...
2017: PloS One
https://www.readbyqxmd.com/read/28445460/polyglutamine-tracts-regulate-beclin-1-dependent-autophagy
#2
Avraham Ashkenazi, Carla F Bento, Thomas Ricketts, Mariella Vicinanza, Farah Siddiqi, Mariana Pavel, Ferdinando Squitieri, Maarten C Hardenberg, Sara Imarisio, Fiona M Menzies, David C Rubinsztein
Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28424476/neurons-export-extracellular-vesicles-enriched-in-cysteine-string-protein-and-misfolded-protein-cargo
#3
Jingti Deng, Carolina Koutras, Julien Donnelier, Mana Alshehri, Maryam Fotouhi, Martine Girard, Steve Casha, Peter S McPherson, Stephen M Robbins, Janice E A Braun
The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28406616/inhibition-of-huntingtin-exon-1-aggregation-by-the-molecular-tweezer-clr01
#4
Tobias Vöpel, Kenny Bravo-Rodriguez, Sumit Mittal, Shivang Vachharajani, David Gnutt, Abhishek Sharma, Anne Steinhof, Oluwaseun Fatoba, Gisa Ellrichmann, Michael Nshanian, Christian Heid, Joseph A Loo, Frank-Gerrit Klärner, Thomas Schrader, Gal Bitan, Erich E Wanker, Simon Ebbinghaus, Elsa Sanchez-Garcia
Huntington's disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htt(e1)). Above a threshold of 37 glutamine residues, htt(e1) starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt(e1) (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt(e1). Here we identify N17 as a potential target for novel therapeutic intervention using the molecular tweezer CLR01...
April 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28400517/aggregation-landscapes-of-huntingtin-exon-1-protein-fragments-and-the-critical-repeat-length-for-the-onset-of-huntington-s-disease
#5
Mingchen Chen, Peter G Wolynes
Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion in the polyglutamine (polyQ) track of the Huntingtin (HTT) protein. The severity of the disease depends on the polyQ repeat length, arising only in patients with proteins having 36 repeats or more. Previous studies have shown that the aggregation of N-terminal fragments (encoded by HTT exon 1) underlies the disease pathology in mouse models and that the HTT exon 1 gene product can self-assemble into amyloid structures. Here, we provide detailed structural mechanisms for aggregation of several protein fragments encoded by HTT exon 1 by using the associative memory, water-mediated, structure and energy model (AWSEM) to construct their free energy landscapes...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28398721/inclusions-of-r6-2-mice-are-not-amyloid-and-differ-structurally-from-those-of-huntington-disease-brain
#6
William André, Christophe Sandt, Isabelle Nondier, Philippe Djian, Guylaine Hoffner
R6/2 mice contain an N-terminal fragment of human huntingtin with an expanded polyQ and develop a neurological disease resembling Huntington disease. Although the brain of R6/2 mice contains numerous inclusions, there is very little neuronal death. In that respect, R6/2 mice differ from patients with Huntington disease whose striatum and cerebral cortex develop inclusions associated with extensive neuronal loss. We have previously demonstrated using synchrotron-based infrared microspectroscopy that the striatum and the cortex of patients with Huntington disease contained inclusions specifically enriched in amyloid β-sheets...
April 24, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28396396/formation-of-neurodegenerative-aggresome-and-death-inducing-signaling-complex-in-maternal-diabetes-induced-neural-tube-defects
#7
Zhiyong Zhao, Lixue Cao, E Albert Reece
Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8-induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28384479/mutant-huntingtin-disrupts-the-nuclear-pore-complex
#8
Jonathan C Grima, J Gavin Daigle, Nicolas Arbez, Kathleen C Cunningham, Ke Zhang, Joseph Ochaba, Charlene Geater, Eva Morozko, Jennifer Stocksdale, Jenna C Glatzer, Jacqueline T Pham, Ishrat Ahmed, Qi Peng, Harsh Wadhwa, Olga Pletnikova, Juan C Troncoso, Wenzhen Duan, Solomon H Snyder, Laura P W Ranum, Leslie M Thompson, Thomas E Lloyd, Christopher A Ross, Jeffrey D Rothstein
Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28368337/crispr-cas9-mediated-gene-silencing-of-the-mutant-huntingtin-gene-in-an-in-vitro-model-of-huntington-s-disease
#9
Nivya Kolli, Ming Lu, Panchanan Maiti, Julien Rossignol, Gray L Dunbar
Huntington's disease (HD) is a fatal neurodegenerative genetic disease characterized by a loss of neurons in the striatum. It is caused by a mutation in the Huntingtin gene (HTT) that codes for the protein huntingtin (HTT). The mutant Huntingtin gene (mHTT) contains extra poly-glutamine (CAG) repeats from which the translated mutant huntingtin proteins (mHTT) undergo inappropriate post-translational modifications, conferring a toxic gain of function, in addition to its non-functional property. In order to curb the production of the mHTT, we have constructed two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associate protein) plasmids, among which one nicks the DNA at untranslated region upstream to the open reading frame (uORF), and the other nicks the DNA at exon1-intron boundary...
April 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28339398/n-terminal-fragments-of-huntingtin-longer-than-residue-170-form-visible-aggregates-independently-to-polyglutamine-expansion
#10
Moore Z Chen, Sue-Ann Mok, Angelique R Ormsby, Paul J Muchowski, Danny M Hatters
BACKGROUND: A hallmark of Huntington's disease is the progressive aggregation of full length and N-terminal fragments of polyglutamine (polyQ)-expanded Huntingtin (Htt) into intracellular inclusions. The production of N-terminal fragments appears important for enabling pathology and aggregation; and hence the direct expression of a variety of N-terminal fragments are commonly used to model HD in animal and cellular models. OBJECTIVE: It remains unclear how the length of the N-terminal fragments relates to polyQ - mediated aggregation...
2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28334749/ctg-repeat-targeting-oligonucleotides-for-down-regulating-huntingtin-expression
#11
Eman M Zaghloul, Olof Gissberg, Pedro M D Moreno, Lee Siggens, Mattias Hällbrink, Anna S Jørgensen, Karl Ekwall, Rula Zain, Jesper Wengel, Karin E Lundin, C I Edvard Smith
Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease...
February 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28306505/identification-of-an-rna-polymerase-iii-regulator-linked-to-disease-associated-protein-aggregation
#12
Olga Sin, Tristan de Jong, Alejandro Mata-Cabana, Michelle Kudron, Mohamad Amr Zaini, Francesco A Aprile, Renée I Seinstra, Esther Stroo, Roméo Willinge Prins, Céline N Martineau, Hai Hui Wang, Wytse Hogewerf, Anne Steinhof, Erich E Wanker, Michele Vendruscolo, Cornelis F Calkhoven, Valerie Reinke, Victor Guryev, Ellen A A Nollen
Protein aggregation is associated with age-related neurodegenerative disorders, such as Alzheimer's and polyglutamine diseases. As a causal relationship between protein aggregation and neurodegeneration remains elusive, understanding the cellular mechanisms regulating protein aggregation will help develop future treatments. To identify such mechanisms, we conducted a forward genetic screen in a C. elegans model of polyglutamine aggregation and identified the protein MOAG-2/LIR-3 as a driver of protein aggregation...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28288000/age-associated-chromatin-relaxation-is-enhanced-in-huntington-s-disease-mice
#13
Myungsun Park, Byungkuk Min, Kyuheum Jeon, Sunwha Cho, Jung Sun Park, Jisun Kim, Jeha Jeon, Jinhoi Song, Seokho Kim, Sangkyun Jeong, Hyemyung Seo, Yong-Kook Kang
Expansion of polyglutamine stretch in the huntingtin (HTT) protein is a major cause of Huntington's disease (HD). The polyglutamine part in HTT interacts with various proteins implicated in epigenetic regulation of genes, suggesting that mutant HTT may disturb the integrity of the epigenetic system. Here, we used a PCRseq-based method to examine expression profile of 395 exonic segments from 260 "epi-driver" genes in splenic T lymphocytes from aged HD mice. We identified 67 exonic segments differentially expressed between young and aged HD mice, most of them upregulated in the aged...
March 12, 2017: Aging
https://www.readbyqxmd.com/read/28282438/a-new-caenorhabditis-elegans-model-of-human-huntingtin-513-aggregation-and-toxicity-in-body-wall-muscles
#14
Amy L Lee, Hailey M Ung, L Paul Sands, Elise A Kikis
Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington's Disease (HD) that is caused by a polyglutamine expansion in the human huntingtin protein (htt). The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells...
2017: PloS One
https://www.readbyqxmd.com/read/28259758/huntingtin-associated-protein-1-hap1-regulates-endocytosis-and-interacts-with-multiple-trafficking-related-proteins
#15
Kimberly D Mackenzie, Yoon Lim, Michael D Duffield, Timothy Chataway, Xin-Fu Zhou, Damien J Keating
Huntingtin-associated protein 1 (HAP1) was initially identified as a binding partner of huntingtin, mutations in which underlie Huntington's disease. Subcellular localization and protein interaction data indicate that HAP1 may be important in vesicle trafficking, cell signalling and receptor internalization. In this study, a proteomics approach was used for the identification of novel HAP1-interacting partners to attempt to shed light on the physiological function of HAP1. Using affinity chromatography with HAP1-GST protein fragments bound to Sepharose columns, this study identified a number of trafficking-related proteins that bind to HAP1...
March 1, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28235896/pathogenic-huntington-alters-bmp-signaling-and-synaptic-growth-through-local-disruptions-of-endosomal-compartments
#16
Yulia Akbergenova, J Troy Littleton
Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) stretch within the Huntingtin (Htt) protein. Pathogenic Htt disrupts multiple neuronal processes, including gene expression, axonal trafficking, proteasome and mitochondrial activity, and intracellular vesicle trafficking. However, the primary pathogenic mechanism and subcellular site of action for mutant Htt are still unclear. Using a Drosophila HD model, we found that pathogenic Htt expression leads to a profound overgrowth of synaptic connections that correlates directly with the levels of Htt at nerve terminals...
March 22, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28211815/generation-and-characterization-of-knock-in-mouse-models-expressing-versions-of-huntingtin-with-either-an-n17-or-a-combined-polyq-and-proline-rich-region-deletion
#17
Emily A André, Elise M Braatz, Jeh-Ping Liu, Scott O Zeitlin
BACKGROUND: The polyglutamine (polyQ) stretch of the Huntingtin protein (HTT) in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR). The PRR is a binding site for many HTT-interacting proteins, and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles. OBJECTIVE: This study investigates the consequence of deleting mouse Huntingtin's (Htt's) N17 domain or a combination of its polyQ stretch and PRR (QP) on normal Htt function in mice...
2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28153533/dysregulation-of-gene-expression-in-the-striatum-of-bachd-rats-expressing-full-length-mutant-huntingtin-and-associated-abnormalities-on-molecular-and-protein-levels
#18
Libo Yu-Taeger, Michael Bonin, Janice Stricker-Shaver, Olaf Riess, Hoa Huu Phuc Nguyen
Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels...
January 30, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28137862/dyrk1a-regulates-hap1-dcaf7-wdr68-binding-with-implication-for-delayed-growth-in-down-syndrome
#19
Jianxing Xiang, Su Yang, Ning Xin, Marta A Gaertig, Roger H Reeves, Shihua Li, Xiao-Jiang Li
Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28132929/identification-of-brain-substrates-of-transglutaminase-by-functional-proteomics-supports-its-role-in-neurodegenerative-diseases
#20
William André, Isabelle Nondier, Maud Valensi, François Guillonneau, Christian Federici, Guylaine Hoffner, Philippe Djian
Transglutaminases are calcium-dependent enzymes that catalyze the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific glutamine and lysine residues. Some transglutaminase isoforms are present in the brain and are thought to participate in the protein aggregation characteristic of neurological diseases such as Huntington, Alzheimer's and Parkinson's disease. We have developed a functional proteomics strategy in which biotinylated amine-donor and amine-acceptor probes were used to identify the transglutaminase substrates present in brain...
May 2017: Neurobiology of Disease
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