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https://www.readbyqxmd.com/read/27871175/epigenetic-changes-in-neurodegenerative-diseases
#1
REVIEW
Min Jee Kwon, Sunhong Kim, Myeong Hoon Han, Sung Bae Lee
Afflicted neurons in various neurodegenerative diseases generally display diverse and complex pathological features before catastrophic occurrence of massive neuronal loss at the late stages of the diseases. This complex nature of neuronal pathophysiology inevitably implicates systemwide changes in basic cellular activities such as transcriptional controls and signal cascades, and so on, as a cause. Recently, as one of these systemwide cellular changes associated with neurodegenerative diseases, epigenetic changes caused by protein toxicity have begun to be highlighted...
November 30, 2016: Molecules and Cells
https://www.readbyqxmd.com/read/27870126/discovery-of-therapeutic-approaches-for-polyglutamine-diseases-a-summary-of-recent-efforts
#2
REVIEW
Sofia Esteves, Sara Duarte-Silva, Patrícia Maciel
Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant...
November 21, 2016: Medicinal Research Reviews
https://www.readbyqxmd.com/read/27851749/the-machado-joseph-disease-deubiquitinase-ataxin-3-regulates-the-stability-and-apoptotic-function-of-p53
#3
Hongmei Liu, Xiaoling Li, Guozhu Ning, Shu Zhu, Xiaolu Ma, Xiuli Liu, Chunying Liu, Min Huang, Ina Schmitt, Ullrich Wüllner, Yamei Niu, Caixia Guo, Qiang Wang, Tie-Shan Tang
As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish...
November 2016: PLoS Biology
https://www.readbyqxmd.com/read/27815841/the-ubiquitin-receptor-adrm1-modulates-hap40-induced-proteasome-activity
#4
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/27807047/candida-albicans-is-resistant-to-polyglutamine-aggregation-and-toxicity
#5
Michelle D Leach, TaeHyung Kim, Sonja DiGregorio, Cathy Collins, Zhaolei Zhang, Martin L Duennwald, Leah E Cowen
Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms, contributing to neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's in humans. Here we examined the effects of polyQ aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of poly-glutamine (polyQ) stretches up to 230Q had no effect on C. albicans ability to grow and withstand proteotoxic stress...
November 2, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27786478/the-aggregation-free-energy-landscapes-of-polyglutamine-repeats
#6
Mingchen Chen, MinYeh Tsai, Weihua Zheng, Peter G Wolynes
Aggregates of proteins containing polyglutamine (polyQ) repeats are strongly associated with several neurodegenerative diseases. The length of the repeats correlates with the severity of the disease. Previous studies have shown that pure polyQ peptides aggregate by nucleated growth polymerization and that the size of the critical nucleus (n*) decreases from tetrameric to dimeric and monomeric as length increases from Q18 to Q26. Why the critical nucleus size changes with repeat-length has been unclear. Using AWSEM (the Associative memory, Water mediated, Structure and Energy Model), we construct the aggregation free energy landscapes for polyQ peptides of different repeat-lengths...
October 27, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27770571/silencing-of-genes-responsible-for-polyq-diseases-using-chemically-modified-single-stranded-sirnas
#7
Agnieszka Fiszer, Marianna E Ellison-Klimontowicz, Wlodzimierz J Krzyzosiak
Polyglutamine (polyQ) diseases comprise a group of nine genetic disorders that are caused by the expansion of the CAG triplet repeat, which encodes glutamine, in unrelated single genes. Various oligonucleotide (ON)-based therapeutic approaches have been considered for polyQ diseases. The very attractive CAG repeat-targeting strategy offers selective silencing of the mutant allele by directly targeting the mutation site. CAG repeat-targeting miRNA-like siRNAs have been shown to specifically inhibit the mutant gene expression, and their characteristic feature is the formation of mismatches in their interactions with the target site...
October 21, 2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27751235/control-of-the-structural-landscape-and-neuronal-proteotoxicity-of-mutant-huntingtin-by-domains-flanking-the-polyq-tract
#8
Koning Shen, Barbara Calamini, Jonathan A Fauerbach, Boxue Ma, Sarah H Shahmoradian, Ivana L Serrano Lachapel, Wah Chiu, Donald C Lo, Judith Frydman
Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation...
October 18, 2016: ELife
https://www.readbyqxmd.com/read/27747217/dnajb6-myopathies-focused-review-on-an-emerging-and-expanding-group-of-myopathies
#9
Alessandra Ruggieri, Simona Saredi, Simona Zanotti, Maria Barbara Pasanisi, Lorenzo Maggi, Marina Mora
Mutations in the DNAJB6 gene have been associated with the autosomal dominant limb girdle muscular dystrophy type 1D (LGMD1D), a disorder characterized by abnormal protein aggregates and rimmed vacuoles in muscle fibers. DNAJB6 is a ubiquitously expressed Hsp40 co-chaperone characterized by a J domain that specifies Hsp70 functions in the cellular environment. DNAJB6 is also a potent inhibitor of expanded polyglutamine (polyQ) aggregation preventing aggregate toxicity in cells. In DNAJB6-mutated patients this anti-aggregation property is significantly reduced, albeit not completely lost...
2016: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/27734565/polyglutamine-toxicity-in-yeast-uncovers-phenotypic-variations-between-different-fluorescent-protein-fusions
#10
Yuwei Jiang, Sonja E DiGregorio, Martin L Duennwald, Patrick Lajoie
The palette of fluorescent proteins (FPs) available for live-cell imaging contains proteins that strongly differ in their biophysical properties. FPs cannot be assumed to be equivalent and in certain cases could significantly perturb the behavior of fluorescent reporters. We employed Saccharomyces cerevisiae to comprehensively study the impact of FPs on the toxicity of polyglutamine (polyQ) expansion proteins associated with Huntington's disease. The toxicity of polyQ fusion constructs is highly dependent on the sequences flanking the polyQ repeats...
October 13, 2016: Traffic
https://www.readbyqxmd.com/read/27721444/multiple-discrete-soluble-aggregates-influence-polyglutamine-toxicity-in-a-huntington-s-disease-model-system
#11
Wen Xi, Xin Wang, Thomas M Laue, Clyde L Denis
Huntington's disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27713486/the-phasor-flim-fingerprints-reveal-shifts-from-oxphos-to-enhanced-glycolysis-in-huntington-disease
#12
Sara Sameni, Adeela Syed, J Lawrence Marsh, Michelle A Digman
Huntington disease (HD) is an autosomal neurodegenerative disorder caused by the expansion of Polyglutamine (polyQ) in exon 1 of the Huntingtin protein. Glutamine repeats below 36 are considered normal while repeats above 40 lead to HD. Impairment in energy metabolism is a common trend in Huntington pathogenesis; however, this effect is not fully understood. Here, we used the phasor approach and Fluorescence Lifetime Imaging Microscopy (FLIM) to measure changes between free and bound fractions of NADH as a indirect measure of metabolic alteration in living cells...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27711049/clozapine-modulates-glucosylceramide-clears-aggregated-proteins-and-enhances-atg8-lc3-in-caenorhabditis-elegans
#13
Limin Hao, Oshrit Ben-David, Suzann M Babb, Anthony H Futerman, Bruce M Cohen, Edgar A Buttner
Defining the mechanisms of action of the antipsychotic drug (APD), clozapine, is of great importance, as clozapine is more effective and has therapeutic benefits in a broader range of psychiatric disorders compared with other APDs. Its range of actions have not been fully characterized. Exposure to APDs early in development causes dose-dependent developmental delay and lethality in Caenorhabditis elegans. A previous genome-wide RNAi screen for suppressors of clozapine-induced developmental delay and lethality revealed 40 candidate genes, including sms-1, which encodes a sphingomyelin synthase...
October 26, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27710941/comparative-analysis-of-anti-polyglutamine-fab-crystals-grown-on-earth-and-in-microgravity
#14
Gwen E Owens, Danielle M New, Alejandra I Olvera, Julia Ashlyn Manzella, Brittney L Macon, Joshua C Dunn, David A Cooper, Robyn L Rouleau, Daniel S Connor, Pamela J Bjorkman
Huntington's disease is one of nine neurodegenerative diseases caused by a polyglutamine (polyQ)-repeat expansion. An anti-polyQ antigen-binding fragment, MW1 Fab, was crystallized both on Earth and on the International Space Station, a microgravity environment where convection is limited. Once the crystals returned to Earth, the number, size and morphology of all crystals were recorded, and X-ray data were collected from representative crystals. The results generally agreed with previous microgravity crystallization studies...
October 1, 2016: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/27702574/cell-free-analysis-of-polyq-dependent-protein-aggregation-and-its-inhibition-by-chaperone-proteins
#15
Kodai Machida, Tomoaki Shigeta, Ayano Kobayashi, Ai Masumoto, Yuna Hidaka, Hiroaki Imataka
Protein misfolding and aggregation is one of the major causes of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. So far protein aggregation related to these diseases has been studied using animals, cultured cells or purified proteins. In this study, we show that a newly synthesized polyglutamine protein implicated in Huntington's disease forms large aggregates in HeLa cells, and successfully recapitulate the process of this aggregation using a translation-based system derived from HeLa cell extracts...
October 1, 2016: Journal of Biotechnology
https://www.readbyqxmd.com/read/27695292/a-triazole-derivative-elicits-autophagic-clearance-of-polyglutamine-aggregation-in-neuronal-cells
#16
Chang Heng Hsieh, Li-Ching Lee, Wai-Yin Leong, Tsai-Chen Yang, Ching-Fa Yao, Kang Fang
Trinucleotide CAG repeat expansion in the coding region of genes has a propensity to form polyglutamine (polyQ) aggregates that contribute to neuronal disorders. Strategies in elevating autophagy to disintegrate the insoluble aggregates without injuring cells have become a major goal for therapy. In this work, a triazole derivative, OC-13, was found accelerating autophagic clearance of polyQ aggregation in human neuroblastoma cells following induction of the enhanced green fluorescence-conjugated chimeric protein that enclosed 79 polyQ repeats (Q79-EGFP)...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27684355/assays-for-the-degradation-of-misfolded-proteins-in-cells
#17
Lili Guo, Wil Prall, Xiaolu Yang
Protein misfolding and aggregation are associated with various neurodegenerative diseases. Cellular mechanisms that recognize and degrade misfolded proteins may serve as potential therapeutic targets. To distinguish degradation of misfolding-prone proteins from other mechanisms that regulate their levels, one important method is to measure protein half-life in cells. However, this can be challenging because misfolding-prone proteins may exist in different forms, including the native form and misfolded forms of distinct characteristics...
2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27681426/rescue-of-metabolic-alterations-in-ar113q-skeletal-muscle-by-peripheral-androgen-receptor-gene-silencing
#18
Elisa Giorgetti, Zhigang Yu, Jason P Chua, Ryosuke Shimamura, Lili Zhao, Fan Zhu, Sriram Venneti, Maria Pennuto, Yuanfang Guan, Gene Hung, Andrew P Lieberman
Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation...
September 27, 2016: Cell Reports
https://www.readbyqxmd.com/read/27677791/cag-expansions-are-genetically-stable-and-form-nontoxic-aggregates-in-cells-lacking-endogenous-polyglutamine-proteins
#19
Ashley A Zurawel, Ruth Kabeche, Sonja E DiGregorio, Lin Deng, Kartikeya M Menon, Hannah Opalko, Martin L Duennwald, James B Moseley, Surachai Supattapone
: Proteins containing polyglutamine (polyQ) regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt) with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington's disease (HD). To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt) in Schizosaccharomyces pombe In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S...
September 27, 2016: MBio
https://www.readbyqxmd.com/read/27647319/triplet-repeat-primed-pcr-tp-pcr-in-molecular-diagnostic-testing-for-spinocerebellar-ataxia-type-3-sca3
#20
Ana Rosa Vieira Melo, Amanda Ramos, Nadiya Kazachkova, Mafalda Raposo, Bruno Filipe Bettencourt, Ana Rita Rendeiro, Teresa Kay, João Vasconcelos, Jácome Bruges-Armas, Manuela Lima
INTRODUCTION AND OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder for which the routine molecular testing is based on PCR and automated capillary electrophoresis. When only a normal allele is detected by standard PCR, the hypothesis of a failed amplification of the expanded allele must be raised. In such cases, complementary techniques such as Southern Blot or triplet repeat primed PCR (TP-PCR) have to be applied. For SCA3, TP-PCR is implemented in some diagnostic laboratories, but a tested protocol has yet to be published...
September 20, 2016: Molecular Diagnosis & Therapy
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