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https://www.readbyqxmd.com/read/29229845/brain-urea-increase-is-an-early-huntington-s-disease-pathogenic-event-observed-in-a-prodromal-transgenic-sheep-model-and-hd-cases
#1
Renee R Handley, Suzanne J Reid, Rudiger Brauning, Paul Maclean, Emily R Mears, Imche Fourie, Stefano Patassini, Garth J S Cooper, Skye R Rudiger, Clive J McLaughlan, Paul J Verma, James F Gusella, Marcy E MacDonald, Henry J Waldvogel, C Simon Bawden, Richard L M Faull, Russell G Snell
The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29225330/huntingtin-gene-repeat-size-variations-affect-risk-of-lifetime-depression
#2
REVIEW
Sarah L Gardiner, Martine J van Belzen, Merel W Boogaard, Willeke M C van Roon-Mom, Maarten P Rozing, Albert M van Hemert, Johannes H Smit, Aartjan T F Beekman, Gerard van Grootheest, Robert A Schoevers, Richard C Oude Voshaar, Raymund A C Roos, Hannie C Comijs, Brenda W J H Penninx, Roos C van der Mast, N Ahmad Aziz
Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons...
December 11, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/29218782/therapy-development-in-huntington-disease-from-current-strategies-to-emerging-opportunities
#3
REVIEW
Audrey S Dickey, Albert R La Spada
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration...
December 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29212816/complete-suppression-of-htt-fibrilization-and-disaggregation-of-htt-fibrils-by-a-trimeric-chaperone-complex
#4
Annika Scior, Alexander Buntru, Kristin Arnsburg, Anne Ast, Manuel Iburg, Katrin Juenemann, Maria Lucia Pigazzini, Barbara Mlody, Dmytro Puchkov, Josef Priller, Erich E Wanker, Alessandro Prigione, Janine Kirstein
Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT). Molecular chaperones have been implicated in suppressing or delaying the aggregation of mutant Htt. Using in vitro and in vivo assays, we have identified a trimeric chaperone complex (Hsc70, Hsp110, and J-protein) that completely suppresses fibrilization of HttExon1Q48 The composition of this chaperone complex is variable as recruitment of different chaperone family members forms distinct functional complexes...
December 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29212711/ppar%C3%AE-activation-by-bexarotene-promotes-neuroprotection-by-restoring-bioenergetic-and-quality-control-homeostasis
#5
Audrey S Dickey, Dafne N Sanchez, Martin Arreola, Kunal R Sampat, Weiwei Fan, Nicolas Arbez, Sergey Akimov, Michael J Van Kanegan, Kohta Ohnishi, Stephen K Gilmore-Hall, April L Flores, Janice M Nguyen, Nicole Lomas, Cynthia L Hsu, Donald C Lo, Christopher A Ross, Eliezer Masliah, Ronald M Evans, Albert R La Spada
Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington's disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model...
December 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29212017/control-of-huntington-s-disease-associated-phenotypes-by-the-striatum-enriched-transcription-factor-foxp2
#6
Lea J Hachigian, Vitor Carmona, Robert J Fenster, Ruth Kulicke, Adrian Heilbut, Annie Sittler, Luís Pereira de Almeida, Jill P Mesirov, Fan Gao, Eric D Kolaczyk, Myriam Heiman
Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29209494/rnai-mechanisms-in-huntington-s-disease-therapy-sirna-versus-shrna
#7
REVIEW
Sebastian Aguiar, Bram van der Gaag, Francesco Albert Bosco Cortese
Huntington's Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (> 36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT)...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29209146/adhesion-regulating-molecule-1-mediates-hap40-overexpression-induced-mitochondrial-defects
#8
Zih-Ning Huang, Her Min Chung, Su-Chiung Fang, Lu-Shiun Her
Striatal neuron death in Huntington's disease is associated with abnormal mitochondrial dynamics and functions. However, the mechanisms for this mitochondrial dysregulation remain elusive. Increased accumulation of Huntingtin-associated protein 40 (HAP40) has been shown to be associated with Huntington's disease. However, the link between increased HAP40 and Huntington's disease remains largely unknown. Here we show that HAP40 overexpression causes mitochondrial dysfunction and reduces cell viability in the immortalized mouse striatal neurons...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29208631/the-drosophila-junctophilin-gene-is-functionally-equivalent-to-its-four-mammalian-counterparts-and-is-a-modifier-of-a-huntingtin-poly-q-expansion-and-the-notch-pathway
#9
Eduardo Calpena, Víctor López Del Amo, Mouli Chakraborty, Beatriz Llamusí, Rubén Artero, Carmen Espinós, Máximo I Galindo
Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells with critical implications for human pathophysiology. In mammals this family consists in four members (JPH1-4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles, and neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in CMT2K peripheral neuropathy...
November 20, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29207890/artificial-mirnas-reduce-human-mutant-huntingtin-throughout-the-striatum-in-a-transgenic-sheep-model-of-huntington-s-disease
#10
Edith Pfister, Natalie Dinardo, Erica Mondo, Florie Borel, Faith Conroy, Cara Fraser, Gwladys Gernoux, Xin Han, Danjing Hu, Emily Johnson, Lori Kennington, PengPeng Liu, Suzanne Reid, Ellen Sapp, Petr Vodicka, Tim Kuchel, A Jennifer Morton, David Howland, Richard Moser, Miguel Sena-Esteves, Guangping Gao, Christian Mueller, Marian DiFiglia, Neil Aronin
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. We used AAV9 to unilaterally deliver to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters- U6 or CβA...
December 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29203806/reduced-cell-size-chromosomal-aberration-and-altered-proliferation-rates-are-characteristics-and-confounding-factors-in-the-sthdh-cell-model-of-huntington-disease
#11
Elisabeth Singer, Carolin Walter, Jonasz J Weber, Ann-Christin Krahl, Ulrike A Mau-Holzmann, Nadine Rischert, Olaf Riess, Laura E Clemensson, Huu P Nguyen
Huntington disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding the huntingtin protein. Expression of the mutant protein disrupts various intracellular pathways and impairs overall cell function. In particular striatal neurons seem to be most vulnerable to mutant huntingtin-related changes. A well-known and commonly used model to study molecular aspects of Huntington disease are the striatum-derived STHdh cell lines generated from wild type and huntingtin knock-in mouse embryos...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29193273/activation-of-caspase-6-and-cleavage-of-caspase-6-substrates-is-an-early-event-in-nmda-receptor-mediated-excitotoxicity
#12
Kimberly D Girling, Marie-Josee Demers, Jean Laine, Shu Zhang, Yu Tian Wang, Rona K Graham
Excitotoxicity, due to overstimulation of N-methyl D-aspartate receptors (NMDARs), has a pivotal role in many neurological disorders. However, NMDAR antagonists often cause side effects, and identifying more druggable therapeutic targets for NMDAR excitotoxicity is an important goal. Activation of caspases is a downstream effect of excitotoxicity that may be critically involved in NMDAR-mediated cell death. Caspase-6 (casp6) in particular has been shown to play a key role in the pathogenesis of stroke, Huntington disease, and Alzheimer disease...
November 29, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/29187283/new-insights-into-transglutaminase-2-and-links-to-neurodegenerative-diseases
#13
Boram Min, Kwang Chul Chung
Formation of toxic protein aggregates is a common feature and mainly contributes to the pathogenesis of neurodegenerative diseases (NDDs), which include amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's, and prion diseases. The transglutaminase 2 (TG2) gene encodes a multifunctional enzyme, displaying four types of activity, such as transamidation, GTPase, protein disulfide isomerase, and protein kinase activities. Many studies demonstrated that the calcium-dependent transamidation activity of TG2 affected the formation of insoluble and toxic amyloid aggregates that mainly consisted of NDD-related proteins...
November 29, 2017: BMB Reports
https://www.readbyqxmd.com/read/29178352/the-use-of-stem-cells-for-understanding-and-treating-huntington-s-disease
#14
REVIEW
Bronwen Connor
Two decades ago, researchers identified that a CAG expansion mutation in the huntingtin (HTT) gene was involved in the pathogenesis of Huntington's disease (HD). However, since the identification of the HTT gene there has been no advance in the development of therapeutic strategies to prevent or reduce the progression of HD. With the recent advances in stem cell biology and human cell reprogramming technologies, several novel and exciting pathways have emerged allowing researchers to enhance their understanding of the pathogenesis of HD, to identify and screen potential drug targets, and to explore alternative donor cell sources for cell replacement therapy...
November 26, 2017: Stem Cells
https://www.readbyqxmd.com/read/29177651/measurement-of-chaperone-mediated-effects-on-polyglutamine-protein-aggregation-by-the-filter-trap-assay
#15
Maria A W H van Waarde-Verhagen, Harm H Kampinga
The formation of aggregates by polyglutamine-containing (polyQ) proteins in neurons is a key to the pathogenesis of several progressive neurodegenerative diseases such as Huntington's disease (HD) spinocerebellar ataxias (SCAs), and spinal and bulbar muscular atrophy (SBMA). In order to study whether the members of the heat shock protein (HSP) families, by virtue of their molecular chaperone activity, can inhibit the formation of polyQ aggregates, we developed a cell culture model expressing the GFP tagged fragment of exon1 of the huntingtin gene with an expanded polyQ chain and tetracycline inducible chaperones...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29172480/myricetin-reduces-toxic-level-of-cag-repeats-rna-in-huntington-s-disease-hd-and-spino-cerebellar-ataxia-scas
#16
Eshan Khan, Arpita Tawani, Subodh Kumar Mishra, Arun Kumar Verma, Arun Upadhyay, Mohit Kumar, Rajat Sandhir, Amit Mishra, Amit Kumar
Huntington's disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of CAG repeats in HTT gene. The transcribed mutant RNA contains expanded CAG repeats that translate into a mutant huntingtin protein. This expanded CAG repeat also causes mis-splicing of pre-mRNA due to sequestration of muscle blind like-1 splicing factor (MBNL1) and thus both of these elicits the pathogenesis of HD. Targeting the onset as well as progression of HD by small molecules could be a potent therapeutic approach...
November 27, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29171910/mutant-huntingtin-protein-expression-and-blood-spinal-cord-barrier-dysfunction-in-huntington-s-disease
#17
Giacomo Sciacca, Francesca Cicchetti
OBJECTIVE: The aim of the study was to assess the distribution, frequency and specific location of mutant huntingtin protein (mHTT) aggregates - the pathological hallmark of HD - within the various compartments of the spinal cord and their potential impact on the local vasculature and BSCB. METHODS: We performed a series of post-mortem immunohistochemical and immunofluorescent stainings, as well as western blot analyses, on cervical and lumbar sections of the spinal cord in patients diagnosed with HD (n=11 of all grades of disease severity) along with sex and age-matched healthy controls (n=9)...
November 24, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29166823/foot-and-mouth-disease-virus-capsid-protein-vp2-activates-the-cellular-eif2s1-atf4-pathway-and-induces-autophagy-via-hspb1
#18
Peng Sun, Shumin Zhang, Xiaodong Qin, Xingni Chang, Xiaorui Cui, Haitao Li, Shuaijun Zhang, Huanghuang Gao, Penghua Wang, Zhidong Zhang, Jianxun Luo
Foot-and-mouth disease virus (FMDV) can result in economical destruction of cloven-hoofed animals. FMDV infection has been reported to induce macroautophagy/autophagy; however, the precise molecular mechanisms of autophagy induction and effect of FMDV capsid protein on autophagy remain unknown. In the present study, we report that FMDV infection induced a complete autophagy process in the natural host cells of FMDV, and inhibition of autophagy significantly decreased FMDV production, suggesting that FMDV-induced autophagy facilitates viral replication...
November 23, 2017: Autophagy
https://www.readbyqxmd.com/read/29166617/spatiotemporal-proteomic-profiling-of-huntington-s-disease-inclusions-reveals-widespread-loss-of-protein-function
#19
Fabian Hosp, Sara Gutiérrez-Ángel, Martin H Schaefer, Jürgen Cox, Felix Meissner, Mark S Hipp, F-Ulrich Hartl, Rüdiger Klein, Irina Dudanova, Matthias Mann
Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington's disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. Extensive remodeling of the soluble brain proteome correlated with insoluble aggregate formation during disease progression...
November 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/29162692/phosphorylation-of-huntingtin-at-residue-t3-is-decreased-in-huntington-s-disease-and-modulates-mutant-huntingtin-protein-conformation
#20
Cristina Cariulo, Lucia Azzollini, Margherita Verani, Paola Martufi, Roberto Boggio, Anass Chiki, Sean M Deguire, Marta Cherubini, Silvia Gines, J Lawrence Marsh, Paola Conforti, Elena Cattaneo, Iolanda Santimone, Ferdinando Squitieri, Hilal A Lashuel, Lara Petricca, Andrea Caricasole
Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples...
November 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
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