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Huntingtin associated Protein

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https://www.readbyqxmd.com/read/28550267/amyloid-precursor-protein-haploinsufficiency-preferentially-mediates-brain-iron-accumulation-in-mice-transgenic-for-the-huntington-s-disease-mutation
#1
Kiersten Berggren, Sonal Agrawal, Julia A Fox, Justin Hildenbrand, Ryan Nelson, Ashley I Bush, Jonathan H Fox
BACKGROUND: Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. OBJECTIVE: To determine the effects of APP insufficiency on HD in YAC128 mice. METHODS: We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny...
May 24, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28532681/resveratrol-protects-neuronal-like-cells-expressing-mutant-huntingtin-from-dopamine-toxicity-by-rescuing-atg4-mediated-autophagosome-formation
#2
Chiara Vidoni, Eleonora Secomandi, Andrea Castiglioni, Mariarosa A B Melone, Ciro Isidoro
Parkinsonian-like motor deficits in Huntington's Disease (HD) patients are associated with abnormal dopamine neurotransmission in the striatum. Dopamine metabolism leads to the formation of oxidized dopamine quinones that exacerbates mitochondrial dysfunction with production of reactive oxygen species (ROS) that eventually lead to neuronal cell death. We have previously shown that dopamine-induced oxidative stress triggers apoptotic cell death in dopaminergic neuroblastoma SH-SY5Y cells hyper-expressing the mutant polyQ Huntingtin (polyQ-Htt) protein...
May 19, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28527044/endocytic-vesicle-rupture-is-a-conserved-mechanism-of-cellular-invasion-by-amyloid-proteins
#3
William P Flavin, Luc Bousset, Zachary C Green, Yaping Chu, Stratos Skarpathiotis, Michael J Chaney, Jeffrey H Kordower, Ronald Melki, Edward M Campbell
Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis...
May 19, 2017: Acta Neuropathologica
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
#4
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/28452374/prognostic-significance-of-huntingtin-interacting-protein-1-expression-on-patients-with-acute-myeloid-leukemia
#5
Jinghan Wang, Mengxia Yu, Qi Guo, Qiuling Ma, Chao Hu, Zhixin Ma, Xiufeng Yin, Xia Li, Yungui Wang, Hanzhang Pan, Dongmei Wang, Jiansong Huang, Haitao Meng, Hongyan Tong, Wenbin Qian, Jie Jin
Huntingtin interacting protein 1 (HIP1) is an endocytic protein which is overexpressed in a variety of human cancers and involved in cancer-causing translocation in leukemia. However, the prognostic impact of HIP1 expression on AML remains unclear. In this study, quantification of HIP1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 270 AML patients. As a result, high HIP1 expression was seen more frequently in older patients, M4/M5 morphology and genes of NPM1 and DNMT3A mutations, and underrepresented in favorable karyotype subgroups and CEBPA double allele mutations in our AML patients...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28445460/polyglutamine-tracts-regulate-beclin-1-dependent-autophagy
#6
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...
May 4, 2017: Nature
https://www.readbyqxmd.com/read/28424476/neurons-export-extracellular-vesicles-enriched-in-cysteine-string-protein-and-misfolded-protein-cargo
#7
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
#8
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 26, 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
#9
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 25, 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
#10
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
#11
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 25, 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
#12
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
#13
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
#14
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
#15
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...
May 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28306505/identification-of-an-rna-polymerase-iii-regulator-linked-to-disease-associated-protein-aggregation
#16
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
#17
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
#18
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
#19
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
#20
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
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