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https://www.readbyqxmd.com/read/27892468/somatic-increase-of-cct8-mimics-proteostasis-of-human-pluripotent-stem-cells-and-extends-c-elegans-lifespan
#1
Alireza Noormohammadi, Amirabbas Khodakarami, Ricardo Gutierrez-Garcia, Hyun Ju Lee, Seda Koyuncu, Tim König, Christina Schindler, Isabel Saez, Azra Fatima, Christoph Dieterich, David Vilchez
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27891320/the-association-of-vdac-with-cell-viability-of-pc12-model-of-huntington-s-disease
#2
Andonis Karachitos, Daria Grobys, Klaudia Kulczyńska, Adrian Sobusiak, Hanna Kmita
It is becoming increasingly apparent that mitochondria dysfunction plays an important role in the pathogenesis of Huntington's disease (HD), but the underlying mechanism is still elusive. Thus, there is a still need for further studies concerning the upstream events in the mitochondria dysfunction that could contribute to cell death observed in HD. Taking into account the fundamental role of the voltage-dependent anion-selective channel (VDAC) in mitochondria functioning, it is reasonable to consider the channel as a crucial element in HD etiology...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27886014/embryonic-mutant-huntingtin-aggregate-formation-in-mouse-models-of-huntington-s-disease
#3
Alexander P Osmand, Terry Jo Bichell, Aaron B Bowman, Gillian P Bates
The role of aggregate formation in the pathophysiology of Huntington's disease (HD) remains uncertain. However, the temporal appearance of aggregates tends to correlate with the onset of symptoms and the numbers of neuropil aggregates correlate with the progression of clinical disease. Using highly sensitive immunohistochemical methods we have detected the appearance of diffuse aggregates during embryonic development in the R6/2 and YAC128 mouse models of HD. These are initially seen in developing axonal tracts and appear to spread throughout the cerebrum in the early neonate...
November 21, 2016: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/27859838/aggregation-induced-changes-in-the-chemical-exchange-saturation-transfer-cest-signals-of-proteins
#4
Steffen Goerke, Katharina S Milde, Raul Bukowiecki, Patrick Kunz, Karel D Klika, Thomas Wiglenda, Axel Mogk, Erich E Wanker, Bernd Bukau, Mark E Ladd, Peter Bachert, Moritz Zaiss
Chemical exchange saturation transfer (CEST) is an MRI technique that allows mapping of biomolecules (small metabolites, proteins) with nearly the sensitivity of conventional water proton MRI. In living organisms, several tissue-specific CEST effects have been observed and successfully applied to diagnostic imaging. In these studies, particularly the signals of proteins showed a distinct correlation with pathological changes. However, as CEST effects depend on various properties that determine and affect the chemical exchange processes, the origins of the observed signal changes remain to be understood...
November 11, 2016: NMR in Biomedicine
https://www.readbyqxmd.com/read/27857176/glycation-potentiates-neurodegeneration-in-models-of-huntington-s-disease
#5
Hugo Vicente Miranda, Marcos António Gomes, Joana Branco-Santos, Carlo Breda, Diana F Lázaro, Luísa Vaqueiro Lopes, Federico Herrera, Flaviano Giorgini, Tiago Fleming Outeiro
Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models...
November 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27853465/epigenetic-dna-methylation-profiling-with-msre-a-quantitative-ngs-approach-using-a-parkinson-s-disease-test-case
#6
Adam G Marsh, Matthew T Cottrell, Morton F Goldman
Epigenetics is a rapidly developing field focused on deciphering chemical fingerprints that accumulate on human genomes over time. As the nascent idea of precision medicine expands to encompass epigenetic signatures of diagnostic and prognostic relevance, there is a need for methodologies that provide high-throughput DNA methylation profiling measurements. Here we report a novel quantification methodology for computationally reconstructing site-specific CpG methylation status from next generation sequencing (NGS) data using methyl-sensitive restriction endonucleases (MSRE)...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27834362/a-novel-neurodevelopmental-disorder-associated-with-compound-heterozygous-variants-in-the-huntingtin-gene
#7
Lance H Rodan, Julie Cohen, Ali Fatemi, Tammy Gillis, Diane Lucente, James Gusella, Jonathan D Picker
No abstract text is available yet for this article.
December 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27824888/bifunctional-anti-non-amyloid-component-%C3%AE-synuclein-nanobodies-are-protective-in-situ
#8
David C Butler, Shubhada N Joshi, Erwin De Genst, Ankit S Baghel, Christopher M Dobson, Anne Messer
Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts...
2016: PloS One
https://www.readbyqxmd.com/read/27824125/a-scfv-antibody-targeting-common-oligomeric-epitope-has-potential-for-treating-several-amyloidoses
#9
Jun Zha, Xiang-Meng Liu, Jie Zhu, Shu-Ying Liu, Shuai Lu, Peng-Xin Xu, Xiao-Lin Yu, Rui-Tian Liu
Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27823570/neurotrophin-receptor-signaling-as-a-therapeutic-target-for-huntington-s-disease
#10
Danielle A Simmons, Frank M Longo, Stephen M Massa
Effective non-genetic disease modifying treatments for Huntington's disease (HD) will necessarily target multiple diverse neurodegenerative processes triggered by mutant huntingtin. Neurotrophin receptors are well-positioned for this task as they regulate signaling pathways that largely overlap with signaling networks contributing to HD-related synaptic dysfunction, glial activation, excitotoxicity, and other degenerative processes. This review will discuss the contributions of disrupted neurotrophin receptor-related signaling to primary HD neuropathologies, and prospects for harnessing this signaling to develop therapeutics to counteract HD degenerative mechanisms...
November 6, 2016: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/27821553/potential-biomarkers-to-follow-the-progression-and-treatment-response-of-huntington-s-disease
#11
Marie-Hélène Disatnik, Amit U Joshi, Nay L Saw, Mehrdad Shamloo, Blair R Leavitt, Xin Qi, Daria Mochly-Rosen
Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27820862/fast-to-slow-transition-of-skeletal-muscle-contractile-function-and-corresponding-changes-in-myosin-heavy-and-light-chain-formation-in-the-r6-2-mouse-model-of-huntington-s-disease
#12
Tanja Hering, Peter Braubach, G Bernhard Landwehrmeyer, Katrin S Lindenberg, Werner Melzer
Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene...
2016: PloS One
https://www.readbyqxmd.com/read/27815841/the-ubiquitin-receptor-adrm1-modulates-hap40-induced-proteasome-activity
#13
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/27811172/tak-063-a-novel-phosphodiesterase-10a-inhibitor-protects-from-striatal-neurodegeneration-and-ameliorates-behavioral-deficits-in-the-r6-2-mouse-model-of-huntington-s-disease
#14
Akina Harada, Kazunori Suzuki, Haruhide Kimura
Huntington's disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling...
November 3, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27809764/cross-phenotype-association-tests-uncover-genes-mediating-nutrient-response-in-drosophila
#15
Christopher S Nelson, Jennifer N Beck, Kenneth A Wilson, Elijah R Pilcher, Pankaj Kapahi, Rachel B Brem
BACKGROUND: Obesity-related diseases are major contributors to morbidity and mortality in the developed world. Molecular diagnostics and targets of therapies to combat nutritional imbalance are urgently needed in the clinic. Invertebrate animals have been a cornerstone of basic research efforts to dissect the genetics of metabolism and nutrient response. We set out to use fruit flies reared on restricted and nutrient-rich diets to identify genes associated with starvation resistance, body mass and composition, in a survey of genetic variation across the Drosophila Genetic Reference Panel (DGRP)...
November 4, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27790650/autophagy-mediated-clearance-of-ubiquitinated-mutant-huntingtin-by-graphene-oxide
#16
Peipei Jin, Pengfei Wei, Yunjiao Zhang, Jun Lin, Rui Sha, Yi Hu, Jiqian Zhang, Wei Zhou, Han Yao, Li Ren, James Y Yang, Yanchun Liu, Longping Wen
Many of the neurodegenerative disorders such as Huntington's disease (HD) are caused by the accumulation of intracytoplasmic aggregate-prone proteins. These toxic protein aggregates are mainly degraded by autophagy, thus elevating the autophagy level to enhance the degradation of these proteins representing an emerging viable approach for the treatment of neurodegenerative diseases. In this report we showed that graphene oxide (GO), an engineered nanomaterial with enormous potential in biomedical applications, effectively enhanced the clearance of mutant huntingtin (Htt), the aggregate-prone protein underlying the pathogenesis of HD...
October 28, 2016: Nanoscale
https://www.readbyqxmd.com/read/27774050/regulation-of-mrna-translation-by-mid1-a-common-mechanism-of-expanded-cag-repeat-rnas
#17
Nadine Griesche, Judith Schilling, Stephanie Weber, Marlena Rohm, Verena Pesch, Frank Matthes, Georg Auburger, Sybille Krauss
Expansion of CAG repeats, which code for the disease-causing polyglutamine protein, is a common feature in polyglutamine diseases. RNA-mediated mechanisms that contribute to neuropathology in polyglutamine diseases are important. RNA-toxicity describes a phenomenon by which the mutant CAG repeat RNA recruits RNA-binding proteins, thereby leading to aberrant function. For example the MID1 protein binds to mutant huntingtin (HTT) RNA, which is linked to Huntington's disease (HD), at its CAG repeat region and induces protein synthesis of mutant protein...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27770571/silencing-of-genes-responsible-for-polyq-diseases-using-chemically-modified-single-stranded-sirnas
#18
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
#19
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 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/27749395/pathogenic-insights-from-huntington-s-disease-like-2-and-other-huntington-s-disease-genocopies
#20
Russell L Margolis, Dobrila D Rudnicki
PURPOSE OF REVIEW: Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease. We review HDL2 pathogenic mechanisms and examine the implications of these mechanisms for Huntington's disease and related diseases. RECENT FINDINGS: HDL2 is caused by a CTG/CAG repeat expansion in junctophilin-3. Available data from cell and animal models and human brain suggest that HDL2 is a complex disease in which transcripts and proteins expressed bidirectionally from the junctophilin-3 locus contribute to pathogenesis through both gain-and loss-of-function mechanisms...
December 2016: Current Opinion in Neurology
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