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https://www.readbyqxmd.com/read/28527044/endocytic-vesicle-rupture-is-a-conserved-mechanism-of-cellular-invasion-by-amyloid-proteins
#1
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/28524599/modulation-of-nuclear-rest-by-alternative-splicing-a-potential-therapeutic-target-for-huntington-s-disease
#2
Guo-Lin Chen, Qi Ma, Dharmendra Goswami, Jianyu Shang, Gregory M Miller
Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting...
May 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28523552/epigenetics-of-huntington-s-disease
#3
Silvia Bassi, Takshashila Tripathi, Alan Monziani, Francesca Di Leva, Marta Biagioli
Huntington's disease (HD) is a genetic, fatal autosomal dominant neurodegenerative disorder typically occurring in midlife with symptoms ranging from chorea, to dementia, to personality disturbances (Philos Trans R Soc Lond Ser B Biol Sci 354:957-961, 1999). HD is inherited in a dominant fashion, and the underlying mutation in all cases is a CAG trinucleotide repeat expansion within exon 1 of the HD gene (Cell 72:971-983, 1993). The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28508341/mitochondrial-dna-levels-in-huntington-disease-leukocytes-and-dermal-fibroblasts
#4
Paulina Jędrak, Magdalena Krygier, Katarzyna Tońska, Małgorzata Drozd, Magdalena Kaliszewska, Ewa Bartnik, Witold Sołtan, Emilia J Sitek, Anna Stanisławska-Sachadyn, Janusz Limon, Jarosław Sławek, Grzegorz Węgrzyn, Sylwia Barańska
Huntington disease (HD) is an inherited neurodegenerative disorder caused by mutations in the huntingtin gene. Involvement of mitochondrial dysfunctions in, and especially influence of the level of mitochondrial DNA (mtDNA) on, development of this disease is unclear. Here, samples of blood from 84 HD patients and 79 controls, and dermal fibroblasts from 10 HD patients and 9 controls were analysed for mtDNA levels. Although the type of mitochondrial haplogroup had no influence on the mtDNA level, and there was no correlation between mtDNA level in leukocytes in HD patients and various parameters of HD severity, some considerable differences between HD patients and controls were identified...
May 16, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28502806/treadmill-exercise-delays-the-onset-of-non-motor-behaviors-and-striatal-pathology-in-the-cag140-knock-in-mouse-model-of-huntington-s-disease
#5
D P Stefanko, V D Shah, W K Yamasaki, G M Petzinger, M W Jakowec
Depression, cognitive impairments, and other neuropsychiatric disturbances are common during the prodromal phase of Huntington's disease (HD) well before the onset of classical motor symptoms of this degenerative disorder. The purpose of this study was to examine the potential impact of physical activity in the form of exercise on a motorized treadmill on non-motor behavioral features including depression-like behavior and cognition in the CAG140 knock-in (KI) mouse model of HD. The CAG140 KI mouse model has a long lifespan compared to other HD rodent models with HD motor deficits emerging after 12months of age and thus provides the opportunity to investigate early life interventions such as exercise on disease progression...
May 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28499347/the-dynamics-of-early-state-transcriptional-changes-and-aggregate-formation-in-a-huntington-s-disease-cell-model
#6
Martijn van Hagen, Diewertje G E Piebes, Wim C de Leeuw, Ilona M Vuist, Willeke M C van Roon-Mom, Perry D Moerland, Pernette J Verschure
BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. Proteolytic cleavage of mutant huntingtin (Htt) protein with an expanded polyglutamine (polyQ) stretch results in production of Htt fragments that aggregate and induce impaired ubiquitin proteasome, mitochondrial functioning and transcriptional dysregulation. To understand the time-resolved relationship between aggregate formation and transcriptional changes at early disease stages, we performed temporal transcriptome profiling and quantification of aggregate formation in living cells in an inducible HD cell model...
May 12, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28497201/huntington-disease-as-a-neurodevelopmental-disorder-and-early-signs-of-the-disease-in-stem-cells
#7
REVIEW
Kalina Wiatr, Wojciech J Szlachcic, Marta Trzeciak, Marek Figlerowicz, Maciej Figiel
Huntington disease (HD) is a dominantly inherited disorder caused by a CAG expansion mutation in the huntingtin (HTT) gene, which results in the HTT protein that contains an expanded polyglutamine tract. The adult form of HD exhibits a late onset of the fully symptomatic phase. However, there is also a long presymptomatic phase, which has been increasingly investigated and recognized as important for the disease development. Moreover, the juvenile form of HD, evoked by a higher number of CAG repeats, resembles a neurodevelopmental disorder and has recently been the focus of additional interest...
May 11, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28495533/microrna-27a-reduces-mutant-hutingtin-aggregation-in-an-in-vitro-model-of-huntington-s-disease
#8
Jae-Jun Ban, Jin-Young Chung, Mijung Lee, Wooseok Im, Manho Kim
Huntington's disease (HD) is a fatal genetic disease caused by abnormal aggregation of mutant huntingtin protein (mHtt). Reduction of mHtt aggregation decreases cell death of the brain and is a promising therapeutic strategy of HD. MicroRNAs are short non-coding nucleotides which modulate various genes and dysregulated in many diseases including HD. MicroRNA miR-27a is reported to be reduced in the brain of R6/2 HD mouse model and modulates multidrug resistance protein-1 (MDR-1). Using subventricular zone-derived neuronal stem cells (NSCs), we used in vitro HD model to test the effect of miR-27a on MDR-1 and mHtt aggregation...
May 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28494017/distinct-cellular-toxicity-of-two-mutant-huntingtin-mrna-variants-due-to-translation-regulation
#9
Haifei Xu, Juan Ji An, Baoji Xu
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion within exon1 of the HTT gene. The gene generates two mRNA variants that carry either a short or long 3' untranslated region (3'UTR) while encoding the same protein. It remains unknown whether the two mRNA variants play distinct roles in HD pathogenesis. We found that the long HTT 3'UTR was capable of guiding mRNA to neuronal dendrites, suggesting that some long-form HTT mRNA is transported to dendrites for local protein synthesis...
2017: PloS One
https://www.readbyqxmd.com/read/28474836/the-ciliary-protein-ift57-in-the-macronucleus-of-paramecium
#10
Lei Shi, Koll France, Olivier Arnaiz, Jean Cohen
The intraflagellar transport IFT57 protein is essential for ciliary growth and maintenance. Also known as HIPPI, human IFT57 can be translocated to the nucleus via a molecular partner of the Huntingtin, Hip1, inducing gene expression changes. In Paramecium tetraurelia, we identified four IFT57 genes forming two subfamilies IFT57A/B and IFT57C/D arising from whole genome duplications. The depletion of proteins of the two subfamilies induced ciliary defects and IFT57A and IFT57C localized in basal bodies and cilia...
May 5, 2017: Journal of Eukaryotic Microbiology
https://www.readbyqxmd.com/read/28469074/sorcs2-mediated-nr2a-trafficking-regulates-motor-deficits-in-huntington-s-disease
#11
Qian Ma, Jianmin Yang, Teresa A Milner, Jean-Paul G Vonsattel, Mary Ellen Palko, Lino Tessarollo, Barbara L Hempstead
Motor dysfunction is a prominent and disabling feature of Huntington's disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein-domain (VPS10P-domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28467905/huntingtin-inclusions-trigger-cellular-quiescence-deactivate-apoptosis-and-lead-to-delayed-necrosis
#12
Yasmin M Ramdzan, Mikhail M Trubetskov, Angelique R Ormsby, Estella A Newcombe, Xiaojing Sui, Mark J Tobin, Marie N Bongiovanni, Sally L Gras, Grant Dewson, Jason M L Miller, Steven Finkbeiner, Nagaraj S Moily, Jonathan Niclis, Clare L Parish, Anthony W Purcell, Michael J Baker, Jacqueline A Wilce, Saboora Waris, Diana Stojanovski, Till Böcking, Ching-Seng Ang, David B Ascher, Gavin E Reid, Danny M Hatters
Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins...
May 2, 2017: Cell Reports
https://www.readbyqxmd.com/read/28465506/the-pathogenic-exon-1-htt-protein-is-produced-by-incomplete-splicing-in-huntington-s-disease-patients
#13
Andreas Neueder, Christian Landles, Rhia Ghosh, David Howland, Richard H Myers, Richard L M Faull, Sarah J Tabrizi, Gillian P Bates
We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington's disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD...
May 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28462988/synthesis-and-evaluation-of-parenchymal-retention-and-efficacy-of-a-metabolically-stable-o-phosphocholine-n-docosahexaenoyl-l-serine-sirna-conjugate-in-mouse-brain
#14
Mehran Nikan, Maire F Osborn, Andrew H Coles, Annabelle Biscans, Bruno Godinho, Reka Haraszti, Ellen Sapp, Dimas Echeverria, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Ligand-conjugated siRNAs have potential to achieve targeted delivery and efficient silencing in neurons following local administration in the central nervous system (CNS). We recently described the activity and safety profile of a docosahexaenoic acid (DHA)-conjugated, hydrophobic siRNA (DHA-hsiRNA) targeting Huntingtin (Htt) mRNA in mouse brain. Here, we report the synthesis of an amide-modified, phosphocholine-containing DHA-hsiRNA conjugate (PC-DHA-hsiRNA), which closely resembles the endogenously esterified biological structure of DHA...
May 2, 2017: Bioconjugate Chemistry
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
#15
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
#16
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/28450110/a-hydrocortisone-derivative-binds-to-gapdh-and-reduces-the-toxicity-of-extracellular-polyglutamine-containing-aggregates
#17
Vladimir F Lazarev, Elena R Mikhaylova, Elizaveta A Dutysheva, Roman V Suezov, Irina V Guzhova, Boris A Margulis
Huntington's disease (HD) has been recently shown to have a horizontally transmitted, prion-like pathology. Thus, the migration of polyglutamine-containing aggregates to acceptor cells is important for the progression of HD. These aggregates contain glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which increases their intracellular transport and their toxicity. Here, we show that RX624, a derivative of hydrocortisone that binds to GAPDH, prevents the formation of aggregates of GAPDH-polyglutamine excreted into the culture medium by PC-12 rat cells expressing mutant huntingtin...
April 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28445460/polyglutamine-tracts-regulate-beclin-1-dependent-autophagy
#18
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/28436437/allele-selective-suppression-of-mutant-huntingtin-in-primary-human-blood-cells
#19
James R C Miller, Edith L Pfister, Wanzhao Liu, Ralph Andre, Ulrike Träger, Lori A Kennington, Kimberly Lo, Sipke Dijkstra, Douglas Macdonald, Gary Ostroff, Neil Aronin, Sarah J Tabrizi
Post-transcriptional gene silencing is a promising therapy for the monogenic, autosomal dominant, Huntington's disease (HD). However, wild-type huntingtin (HTT) has important cellular functions, so the ideal strategy would selectively lower mutant HTT while sparing wild-type. HD patients were genotyped for heterozygosity at three SNP sites, before phasing each SNP allele to wild-type or mutant HTT. Primary ex vivo myeloid cells were isolated from heterozygous patients and transfected with SNP-targeted siRNA, using glucan particles taken up by phagocytosis...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424652/quantitative-electroencephalographic-biomarkers-in-preclinical-and-human-studies-of-huntington-s-disease-are-they-fit-for-purpose-for-treatment-development
#20
REVIEW
Michael K Leuchter, Elissa J Donzis, Carlos Cepeda, Aimee M Hunter, Ana María Estrada-Sánchez, Ian A Cook, Michael S Levine, Andrew F Leuchter
A major focus in development of novel therapies for Huntington's disease (HD) is identification of treatments that reduce the burden of mutant huntingtin (mHTT) protein in the brain. In order to identify and test the efficacy of such therapies, it is essential to have biomarkers that are sensitive to the effects of mHTT on brain function to determine whether the intervention has been effective at preventing toxicity in target brain systems before onset of clinical symptoms. Ideally, such biomarkers should have a plausible physiologic basis for detecting the effects of mHTT, be measureable both in preclinical models and human studies, be practical to measure serially in clinical trials, and be reliably measurable in HD gene expansion carriers (HDGECs), among other features...
2017: Frontiers in Neurology
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