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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/29772202/rnp-granule-assembly-via-ataxin-2-disordered-domains-is-required-for-long-term-memory-and-neurodegeneration
#2
Baskar Bakthavachalu, Joern Huelsmeier, Indulekha P Sudhakaran, Jens Hillebrand, Amanjot Singh, Arnas Petrauskas, Devasena Thiagarajan, M Sankaranarayanan, Laura Mizoue, Eric N Anderson, Udai Bhan Pandey, Eric Ross, K VijayRaghavan, Roy Parker, Mani Ramaswami
Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo...
May 16, 2018: Neuron
https://www.readbyqxmd.com/read/29769649/organoruthenium-ii-complexes-ameliorates-oxidative-stress-and-impedes-the-age-associated-deterioration-in-caenorhabditis-elegans-through-jnk-1-daf-16-signalling
#3
G Devagi, A Mohankumar, G Shanmugam, S Nivitha, F Dallemer, P Kalaivani, P Sundararaj, R Prabhakaran
New ruthenium(II) complexes were synthesised and characterized by various spectro analytical techniques. The structure of the complexes 3 and 4 has been confirmed by X-ray crystallography. The complexes were subjected to study their anti-oxidant profile and were exhibited significantly greater in vitro DPPH radical scavenging activity than vitamin C. We found that complexes 1-4 confered tolerance to oxidative stress and extend the mean lifespan of mev-1 mutant worms and wild-type Caenorhabditis elegans. Further, mechanistic study and reporter gene expression analysis revealed that Ru(ƞ6 -p-cymene) complexes maintained the intracellular redox status and offers stress resistance through activating JNK-1/DAF-16 signaling axis and possibly by other antioxidant response pathway...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29760078/chaperone-ampylation-modulates-aggregation-and-toxicity-of-neurodegenerative-disease-associated-polypeptides
#4
Matthias C Truttmann, David Pincus, Hidde L Ploegh
Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn)...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29758256/reduction-of-protein-kinase-a-mediated-phosphorylation-of-atxn1-s776-in-purkinje-cells-delays-onset-of-ataxia-in-a-sca1-mouse-model
#5
Judit M Pérez Ortiz, Nissa Mollema, Nicholas Toker, Carolyn J Adamski, Brennon O'Callaghan, Lisa Duvick, Jillian Friedrich, Michael A Walters, Jessica Strasser, Jon E Hawkinson, Huda Y Zoghbi, Christine Henzler, Harry T Orr, Sarita Lagalwar
Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation...
May 11, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29754822/a-liquid-to-solid-phase-transition-underlying-pathological-huntingtin-exon1-aggregation
#6
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/29727175/interaction-of-huntingtin-exon-1-peptides-with-lipid-based-micellar-nanoparticles-probed-by-solution-nmr-and-q-band-pulsed-epr
#7
Alberto Ceccon, Thomas Schmidt, Vitali Tugarinov, Samuel A Kotler, Charles D Schwieters, G Marius Clore
Lipid-based micellar nanoparticles promote aggregation of huntingtin exon-1 peptides. Here we characterize the interaction of two such peptides, httNTQ7 and httNTQ10 comprising the N-terminal amphiphilic domain of huntingtin followed by 7 and 10 glutamine repeats, respectively, with 8 nm lipid micelles using NMR chemical exchange saturation transfer (CEST), circular dichroism and pulsed Q-band EPR. Exchange between free and micelle-bound httNTQn peptides occurs on the millisecond time scale with a KD ~ 0.5-1 mM...
May 4, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29726932/glial-expression-of-disease-associated-poly-glutamine-proteins-impairs-the-blood-brain-barrier-in-drosophila
#8
Po-An Yeh, Ya-Hsin Liu, Wei-Chen Chu, Jia-Yu Liu, Y Henry Sun
Expansion of poly-glutamine (polyQ) stretches in several proteins has been linked to neurodegenerative diseases. The effects of polyQ-expanded proteins on neurons have been extensively studied, but their effects on glia remain unclear. We found that expression of distinct polyQ proteins exclusively in all glia or specifically in the blood-brain barrier (BBB) and blood-retina barrier (BRB) glia caused cell-autonomous impairment of BBB/BRB integrity, suggesting that BBB/BRB glia are most vulnerable to polyQ-expanded proteins...
May 2, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29715545/multiple-system-atrophy-and-cag-repeat-length-a-genetic-screening-of-polyglutamine-disease-genes-in-italian-patients
#9
Alessia Mongelli, Lidia Sarro, Elena Rizzo, Lorenzo Nanetti, Nicoletta Meucci, Gianni Pezzoli, Stefano Goldwurm, Franco Taroni, Caterina Mariotti, Cinzia Gellera
Multiple system atrophy (MSA) is an adult onset, progressive, neurodegenerative disorder of unknown etiology characterized by autonomic dysfunction, parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). The phenotypic spectrum may present overlapping features with other neurodegenerative diseases, particularly the autosomal dominant inherited polyglutamine disorders. To investigate the possible contribution of CAG expansions in the MSA phenotype, we analyzed the triplet repeat length in the autosomal dominant causative genes for spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy (DRPLA) and Huntington disease (HD) in a cohort of 246 Italian MSA patients...
April 28, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29704548/toxicity-and-aggregation-of-the-polyglutamine-disease-protein-ataxin-3-is-regulated-by-its-binding-to-vcp-p97-in-drosophila-melanogaster
#10
Gorica Ristic, Joanna R Sutton, Kozeta Libohova, Sokol V Todi
Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat...
April 25, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29694863/insights-into-the-aggregation-mechanism-of-polyq-proteins-with-different-glutamine-repeat-lengths
#11
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/29661116/crispr-cas9-targeted-deletion-of-polyglutamine-in-spinocerebellar-ataxia-type-3-derived-induced-pluripotent-stem-cells
#12
Shuming Ouyang, Yingjun Xie, Zeyu Xiong, Yi Yang, Yexing Xian, Zhanhui Ou, Bing Song, Yuchang Chen, Yuhuan Xie, Haoxian Li, Xiaofang Sun
Spinocerebellar ataxia type 3 (SCA3) is caused by an abnormal expansion of the CAG triplet in ATXN3, which translates into a polyglutamine (polyQ) tract within ataxin-3 (ATXN3) protein. Although the pathogenic mechanisms remain unclear, it is well established that expression of mutant forms of ATXN3 carrying an expanded polyQ domain are involved in SCA3 pathogenesis, and several strategies to suppress mutant ATXN3 have showed promising potential for SCA3 treatment. In this study, we described successful CRISPR/Cas9-mediated deletion of the expanded polyQ-encoding region of ATXN3 in induced pluripotent stem cells (iPSCs) derived from a SCA3 patient, and these patient-specific iPSCs retained pluripotency and neural differentiation following expanded polyQ deletion...
April 17, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29650703/mrna-structure-determines-specificity-of-a-polyq-driven-phase-separation
#13
Erin M Langdon, Yupeng Qiu, Amirhossein Ghanbari Niaki, Grace A McLaughlin, Chase Weidmann, Therese M Gerbich, Jean A Smith, John M Crutchley, Christina M Termini, Kevin M Weeks, Sua Myong, Amy S Gladfelter
RNA promotes liquid-liquid phase separation (LLPS) to build membraneless compartments in cells. How distinct molecular compositions are established and maintained in these liquid compartments is unknown. Here, we report that secondary structure allows mRNAs to self-associate and determines whether an mRNA is recruited to or excluded from liquid compartments. The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence. These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity...
April 12, 2018: Science
https://www.readbyqxmd.com/read/29627459/tadpole-like-conformations-of-huntingtin-exon-1-are-characterized-by-conformational-heterogeneity-that-persists-regardless-of-polyglutamine-length
#14
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/29619771/a-study-of-triplet-primed-pcr-for-identification-of-cag-repeat-expansion-in-the-htt-gene-in-a-cohort-of-503-indian-cases-with-huntington-s-disease-symptoms
#15
Pratiksha Chheda, Milind Chanekar, Yogita Salunkhe, Tavisha Dama, Anurita Pais, Shailesh Pande, Rajesh Bendre, Nilesh Shah
BACKGROUND: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder with an average age at onset of 40 years. It is a polyglutamine (polyQ) disorder that is caused by an increase in the number of CAG repeats in the huntingtin (HTT) gene. Genetic tests that accurately determine the number of CAG repeats are performed for confirmation of diagnosis, predictive testing of persons at genetic risk for inheriting HD, and prenatal testing. The aim of our study was to evaluate efficacy of triplet-primed polymerase chain reaction (TP-PCR) for routine diagnosis of HD in suspected cases from India...
April 4, 2018: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/29608721/glutamine-codon-usage-and-polyq-evolution-in-primates-depend-on-the-q-stretch-length
#16
Pablo Mier, Miguel A Andrade-Navarro
Amino acid usage in a proteome depends mostly on its taxonomy, as it does the codon usage in transcriptomes. Here, we explore the level of variation in the codon usage of a specific amino acid, glutamine, in relation to the number of consecutive glutamine residues. We show that CAG triplets are consistently more abundant in short glutamine homorepeats (polyQ, four to eight residues) than in shorter glutamine stretches (one to three residues), leading to the evolutionary growth of the repeat region in a CAG-dependent manner...
March 1, 2018: Genome Biology and Evolution
https://www.readbyqxmd.com/read/29601786/self-assembly-of-mutant-huntingtin-exon-1-fragments-into-large-complex-fibrillar-structures-involves-nucleated-branching
#17
Anne S Wagner, Antonio Z Politi, Anne Ast, Kenny Bravo-Rodriguez, Katharina Baum, Alexander Buntru, Nadine U Strempel, Lydia Brusendorf, Christian Hänig, Annett Boeddrich, Stephanie Plassmann, Konrad Klockmeier, Juan M Ramirez-Anguita, Elsa Sanchez-Garcia, Jana Wolf, Erich E Wanker
Huntingtin (HTT) fragments with extended polyglutamine (polyQ) tracts self-assemble into amyloid-like fibrillar aggregates. Elucidating the fibril formation mechanism is critical for understanding Huntington's disease pathology and for developing novel therapeutic strategies. Here, we performed systematic experimental and theoretical studies to examine the self-assembly of an aggregation-prone N-terminal HTT exon-1 fragment with 49 glutamines (Ex1Q49). Using high resolution imaging techniques such as electron microscopy and atomic force microscopy, we show that Ex1Q49 fragments in cell-free assays spontaneously convert into large, highly complex bundles of amyloid fibrils with multiple ends and fibril branching points...
March 27, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29581260/molecular-and-structural-architecture-of-polyq-aggregates-in-yeast
#18
Anselm Gruber, Daniel Hornburg, Matthias Antonin, Natalie Krahmer, Javier Collado, Miroslava Schaffer, Greta Zubaite, Christian Lüchtenborg, Timo Sachsenheimer, Britta Brügger, Matthias Mann, Wolfgang Baumeister, F Ulrich Hartl, Mark S Hipp, Rubén Fernández-Busnadiego
Huntington's disease is caused by the expansion of a polyglutamine (polyQ) tract in the N-terminal exon of huntingtin (HttEx1), but the cellular mechanisms leading to neurodegeneration remain poorly understood. Here we present in situ structural studies by cryo-electron tomography of an established yeast model system of polyQ toxicity. We find that expression of polyQ-expanded HttEx1 results in the formation of unstructured inclusion bodies and in some cases fibrillar aggregates. This contrasts with recent findings in mammalian cells, where polyQ inclusions were exclusively fibrillar...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29570305/interaction-enthalpy-of-side-chain-and-backbone-amides-in-polyglutamine-solution-monomers-and-fibrils
#19
David Punihaole, Ryan S Jakubek, Riley J Workman, Sanford A Asher
We determined an empirical correlation that relates the Amide I vibrational band frequencies of the glutamine (Q) side chain to the strength of hydrogen bonding, van der Waals, and Lewis acid-base interactions of its primary amide carbonyl. We use this correlation to determine the Q side chain carbonyl interaction enthalpy (ΔHint) in monomeric and amyloid-like fibril conformations of D2Q10K2 (Q10). We independently verified these ΔHint values through molecular dynamics simulations that showed excellent agreement with experiments...
March 23, 2018: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/29535594/precise-excision-of-the-cag-tract-from-the-huntingtin-gene-by-cas9-nickases
#20
Magdalena Dabrowska, Wojciech Juzwa, Wlodzimierz J Krzyzosiak, Marta Olejniczak
Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the first exon of the huntingtin gene ( HTT ). The accumulation of polyglutamine-rich huntingtin proteins affects various cellular functions and causes selective degeneration of neurons in the striatum. Therapeutic strategies used to date to silence the expression of mutant HTT include antisense oligonucleotides, RNA interference-based approaches and, recently, genome editing with the CRISPR/Cas9 system...
2018: Frontiers in Neuroscience
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