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https://www.readbyqxmd.com/read/28408866/post-translational-modifications-and-protein-quality-control-in-motor-neuron-and-polyglutamine-diseases
#1
REVIEW
Fabio Sambataro, Maria Pennuto
Neurodegenerative diseases, including motor neuron and polyglutamine (polyQ) diseases, are a broad class of neurological disorders. These diseases are characterized by neuronal dysfunction and death, and by the accumulation of toxic aggregation-prone proteins in the forms of inclusions and micro-aggregates. Protein quality control is a cellular mechanism to reduce the burden of accumulation of misfolded proteins, a function that results from the coordinated actions of chaperones and degradation systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosomal degradation system...
2017: Frontiers in Molecular Neuroscience
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
#2
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/the-inclusions-of-r6-2-mice-are-not-amyloid-and-differ-structurally-from-those-of-huntington-disease-brain
#3
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 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28386214/chaperones-in-polyglutamine-aggregation-beyond-the-q-stretch
#4
REVIEW
E F E Kuiper, Eduardo P de Mattos, Laura B Jardim, Harm H Kampinga, Steven Bergink
Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28375147/crystal-structures-of-hsp104-n-terminal-domains-from-saccharomyces-cerevisiae-and-candida-albicans-suggest-the-mechanism-for-the-function-of-hsp104-in-dissolving-prions
#5
Peng Wang, Jingzhi Li, Clarissa Weaver, Aaron Lucius, Bingdong Sha
Hsp104 is a yeast member of the Hsp100 family which functions as a molecular chaperone to disaggregate misfolded polypeptides. To understand the mechanism by which the Hsp104 N-terminal domain (NTD) interacts with its peptide substrates, crystal structures of the Hsp104 NTDs from Saccharomyces cerevisiae (ScHsp104NTD) and Candida albicans (CaHsp104NTD) have been determined at high resolution. The structures of ScHsp104NTD and CaHsp104NTD reveal that the yeast Hsp104 NTD may utilize a conserved putative peptide-binding groove to interact with misfolded polypeptides...
April 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28374014/transgenic-monkey-model-of-the-polyglutamine-diseases-recapitulating-progressive-neurological-symptoms
#6
Ikuo Tomioka, Hidetoshi Ishibashi, Eiko N Minakawa, Hideyuki H Motohashi, Osamu Takayama, Yuko Saito, H Akiko Popiel, Sandra Puentes, Kensuke Owari, Terumi Nakatani, Naotake Nogami, Kazuhiro Yamamoto, Satoru Noguchi, Takahiro Yonekawa, Yoko Tanaka, Naoko Fujita, Hikaru Suzuki, Hisae Kikuchi, Shu Aizawa, Seiichi Nagano, Daisuke Yamada, Ichizo Nishino, Noritaka Ichinohe, Keiji Wada, Shinichi Kohsaka, Yoshitaka Nagai, Kazuhiko Seki
Age-associated neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28357370/attenuation-of-polyglutamine-induced-toxicity-by-enhancement-of-mitochondrial-oxphos-in-yeast-and-fly-models-of-aging
#7
Andrea L Ruetenik, Alejandro Ocampo, Kai Ruan, Yi Zhu, Chong Li, R Grace Zhai, Antoni Barrientos
Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which HAP4 overexpression exerts this protection remains unclear...
July 26, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28339398/n-terminal-fragments-of-huntingtin-longer-than-residue-170-form-visible-aggregates-independently-to-polyglutamine-expansion
#8
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/28333578/hormetic-heat-shock-and-hsf-1-overexpression-improve-c-elegans-survival-and-proteostasis-by-inducing-autophagy
#9
Caroline Kumsta, Malene Hansen
The cellular recycling process of macroautophagy/autophagy is an essential homeostatic system induced by various stresses, but it remains unclear how autophagy contributes to organismal stress resistance. In a recent study, we report that a mild and physiologically beneficial ("hormetic") heat shock as well as overexpression of the heat-shock responsive transcription factor HSF-1 systemically increases autophagy in C. elegans. Accordingly, we found HSF-1- and heat stress-inducible autophagy to be required for C...
March 23, 2017: Autophagy
https://www.readbyqxmd.com/read/28327982/the-role-of-ar-polyq-tract-in-male-breast-carcinoma-lesson-from-a-sbma-case
#10
Giorgia Querin, Ilaria Martinelli, Cinzia Bertolin, Elena Pegoraro, Maria Pennuto, Gianni Sorarù
No abstract text is available yet for this article.
February 28, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28319202/evolving-notch-polyq-tracts-reveal-possible-solenoid-interference-elements
#11
Albert J Erives
Polyglutamine (polyQ) tracts in regulatory proteins are extremely polymorphic. As functional elements under selection for length, triplet repeats are prone to DNA replication slippage and indel mutations. Many polyQ tracts are also embedded within intrinsically disordered domains, which are less constrained, fast evolving, and difficult to characterize. To identify structural principles underlying polyQ tracts in disordered regulatory domains, here I analyze deep evolution of metazoan Notch polyQ tracts, which can generate alleles causing developmental and neurogenic defects...
2017: PloS One
https://www.readbyqxmd.com/read/28281930/combined-trna-modification-defects-impair-protein-homeostasis-and-synthesis-of-the-yeast-prion-protein-rnq1
#12
Raffael Schaffrath, Roland Klassen
Modified nucleosides in tRNA anticodon loops such as 5-methoxy-carbonyl-methyl-2-thiouridine (mcm(5)s(2)U) and pseuduridine (Ψ) are thought to be required for an efficient decoding process. In Saccharomyces cerevisiae, the simultaneous presence of mcm(5)s(2)U and Ψ38 in tRNA(Gln)UUG was shown to mediate efficient synthesis of the Q/N rich [PIN(+)] prion forming protein Rnq1. (1) In the absence of these two tRNA modifications, higher than normal levels of hypomodified tRNA(Gln)UUG, but not its isoacceptor tRNA(Gln)CUG can restore Rnq1 synthesis...
January 2, 2017: Prion
https://www.readbyqxmd.com/read/28263187/aggregation-of-scaffolding-protein-disc1-dysregulates-phosphodiesterase-4-in-huntington-s-disease
#13
Motomasa Tanaka, Koko Ishizuka, Yoko Nekooki-Machida, Ryo Endo, Noriko Takashima, Hideyuki Sasaki, Yusuke Komi, Amy Gathercole, Elaine Huston, Kazuhiro Ishii, Kelvin Kai-Wan Hui, Masaru Kurosawa, Sun-Hong Kim, Nobuyuki Nukina, Eiki Takimoto, Miles D Houslay, Akira Sawa
Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice)...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28235896/pathogenic-huntington-alters-bmp-signaling-and-synaptic-growth-through-local-disruptions-of-endosomal-compartments
#14
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
#15
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/28202696/low-cancer-prevalence-in-polyglutamine-expansion-diseases
#16
Giulia Coarelli, Alhassane Diallo, Morgane Sonia Thion, Daisy Rinaldi, Fabienne Calvas, Ouahid Lagha Boukbiza, Alina Tataru, Perrine Charles, Christine Tranchant, Cecilia Marelli, Claire Ewenczyk, Maya Tchikviladzé, Marie-Lorraine Monin, Bertrand Carlander, Mathieu Anheim, Alexis Brice, Fanny Mochel, Sophie Tezenas du Montcel, Sandrine Humbert, Alexandra Durr
OBJECTIVE: Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France. METHODS: Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier...
March 21, 2017: Neurology
https://www.readbyqxmd.com/read/28198373/hormetic-heat-stress-and-hsf-1-induce-autophagy-to-improve-survival-and-proteostasis-in-c-elegans
#17
Caroline Kumsta, Jessica T Chang, Jessica Schmalz, Malene Hansen
Stress-response pathways have evolved to maintain cellular homeostasis and to ensure the survival of organisms under changing environmental conditions. Whereas severe stress is detrimental, mild stress can be beneficial for health and survival, known as hormesis. Although the universally conserved heat-shock response regulated by transcription factor HSF-1 has been implicated as an effector mechanism, the role and possible interplay with other cellular processes, such as autophagy, remains poorly understood...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28170216/proteins-containing-expanded-polyglutamine-tracts-and-neurodegenerative-disease
#18
Adewale Adegbuyiro, Faezeh Sedighi, Albert W Pilkington, Sharon Groover, Justin Legleiter
Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been 10 of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease...
February 21, 2017: Biochemistry
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
#19
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/28142290/nanoparticulate-strategies-for-the-treatment-of-polyglutamine-diseases-by-halting-the-protein-aggregation-process-%C3%A2
#20
Oscar Escalona-Rayo, Paulina Fuentes-Vázquez, Gerardo Leyva-Gómez, Bulmaro Cisneros, Rafael Villalobos, Jonathan J Magaña, David Quintanar-Guerrero
Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood-brain barrier (BBB)...
June 2017: Drug Development and Industrial Pharmacy
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