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https://www.readbyqxmd.com/read/29325609/the-cag-polyglutamine-repeat-diseases-a-clinical-molecular-genetic-and-pathophysiologic-nosology
#1
Colleen A Stoyas, Albert R La Spada
Throughout the genome, unstable tandem nucleotide repeats can expand to cause a variety of neurologic disorders. Expansion of a CAG triplet repeat within a coding exon gives rise to an elongated polyglutamine (polyQ) tract in the resultant protein product, and accounts for a unique category of neurodegenerative disorders, known as the CAG-polyglutamine repeat diseases. The nine members of the CAG-polyglutamine disease family include spinal and bulbar muscular atrophy (SBMA), Huntington disease, dentatorubral pallidoluysian atrophy, and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17)...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29318784/divalproex-sodium-modulates-nuclear-localization-of-ataxin-3-and-prevents-cellular-toxicity-caused-by-expanded-ataxin-3
#2
Zi-Jian Wang, Aoife Hanet, Daniel Weishäupl, Inês M Martins, Anna S Sowa, Olaf Riess, Thorsten Schmidt
BACKGROUND & AIMS: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal dominantly inherited neurodegenerative disorder and the most common form of SCA worldwide. It is caused by the expansion of a polyglutamine (polyQ) tract in the ataxin-3 protein. Nuclear localization of the affected protein is a key event in the pathology of SCA3 via affecting nuclear organization, transcriptional dysfunction, and seeding aggregations, finally causing neurodegeneration and cell death...
January 9, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29302199/cell-to-cell-transmission-of-polyglutamine-aggregates-in-c-elegans
#3
Dong-Kyu Kim, Kyu-Won Cho, Woo Jung Ahn, Dayana Perez-Acuña, Hyunsu Jeong, He-Jin Lee, Seung-Jae Lee
Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor and cognitive dysfunction caused by expansion of polyglutamine (polyQ) repeat in exon 1 of huntingtin (HTT). In patients, the number of glutamine residues in polyQ tracts are over 35, and it is correlated with age of onset, severity, and disease progression. Expansion of polyQ increases the propensity for HTT protein aggregation, process known to be implicated in neurodegeneration. These pathological aggregates can be transmitted from neuron to another neuron, and this process may explain the pathological spreading of polyQ aggregates...
December 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/29295891/a-peptidylic-inhibitor-for-neutralizing-expanded-cag-rna-induced-nucleolar-stress-in-polyglutamine-diseases
#4
Qian Zhang, Zhefan Stephen Chen, Ying An, Haizhen Liu, Yonghui Hou, Wen Li, Kwok-Fai Lau, Alex Koon, Jacky Ngo, Edwin Chan
Polyglutamine (polyQ) diseases are a set of progressive neurodegenerative disorders ascribed by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) leads to impediment of pre-ribosomal RNA (pre-rRNA) transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report a 21-amino acid peptide, named beta-structured inhibitor for neurodegenerative disease (BIND), effectively suppresses expanded CAG RNA toxicity...
January 2, 2018: RNA
https://www.readbyqxmd.com/read/29282287/the-17-residue-long-n-terminus-in-huntingtin-controls-step-wise-aggregation-in-solution-and-on-membranes-via-different-mechanisms
#5
Nitin K Pandey, J Mario Isas, Anoop Rawat, Rachel V Lee, Jennifer Langen, Priyatama Pandey, Ralf Langen
Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: (1) unseeded in solution, (2) seeded in solution, and (3) membrane-mediated...
December 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29249939/co-expression-patterns-between-atn1-and-atxn2-coincide-with-brain-regions-affected-in-huntington-s-disease
#6
Arlin Keo, N Ahmad Aziz, Oleh Dzyubachyk, Jeroen van der Grond, Willeke M C van Roon-Mom, Boudewijn P F Lelieveldt, Marcel J T Reinders, Ahmed Mahfouz
Cytosine-adenine-guanine (CAG) repeat expansions in the coding regions of nine polyglutamine (polyQ) genes (HTT, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATN1, AR, and TBP) are the cause of several neurodegenerative diseases including Huntington's disease (HD), six different spinocerebellar ataxias (SCAs), dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy. The expanded CAG repeat length in the causative gene is negatively related to the age-at-onset (AAO) of clinical symptoms. In addition to the expanded CAG repeat length in the causative gene, the normal CAG repeats in the other polyQ genes can affect the AAO, suggesting functional interactions between the polyQ genes...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29247688/caffeic-acid-and-resveratrol-ameliorate-cellular-damage-in-cell-and-drosophila-models-of-spinocerebellar-ataxia-type-3-through-upregulation-of-nrf2-pathway
#7
Yu-Ling Wu, Jui-Chih Chang, Wei-Yong Lin, Chien-Chun Li, Mingli Hsieh, Haw-Wen Chen, Tsu-Shing Wang, Wen-Tzu Wu, Chin-San Liu, Kai-Li Liu
Polyglutamine (polyQ)-expanded mutant ataxin-3 protein, which is prone to misfolding and aggregation, leads to cerebellar neurotoxicity in spinocerebellar ataxia type 3 (SCA3), an inherited PolyQ neurodegenerative disease. Although the exact mechanism is unknown, the pathogenic effects of mutant ataxin-3 are associated with dysregulation of transcription, protein degradation, mitochondrial function, apoptosis, and antioxidant potency. In the present study we explored the protective role and possible mechanism of caffeic acid (CA) and resveratrol (Res) in cells and Drosophila expressing mutant ataxin-3...
December 13, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29232946/huntingtin-polyglutamine-dependent-protein-aggregation-in-reconstituted-cells
#8
Kodai Machida, Kuru Kanzawa, Tomoaki Shigeta, Yuki Yamamoto, Kanta Tsumoto, Hiroaki Imataka
One of the aims of synthetic biology is bottom-up construction of reconstituted human cells for medical uses. To that end, we generated giant unilamella vesicles (GUVs) that contained a HeLa cell extract, which comprises a cell-free protein synthesis (CFPS) system. Then we expressed Huntingtin protein fragments that contained polyglutamine (polyQ) sequences (Htt-polyQ), a hallmark of Huntington's disease. That system produced polyQ-dependent protein aggregates, as previously demonstrated in living cells. We next simplified the system by generating GUVs that contained purified human factors, which reconstituted a CFPS system...
December 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29229556/experimental-and-clinical-strategies-for-treating-spinocerebellar-ataxia-type-3
#9
REVIEW
Zijian Wang
Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) tract in the ataxin-3 protein. To date, there is no effective therapy available to prevent progression of this disease. However, clinical strategies for alleviating various symptoms are imperative to promote a better quality of life for SCA3/MJD patients. Furthermore, experimental therapeutic strategies, including gene silencing or mutant protein clearance, mutant polyQ protein modification, stabilizing the native protein conformation, rescue of cellular dysfunction and neuromodulation to slow the progression of SCA3/MJD, have been developed...
December 8, 2017: Neuroscience
https://www.readbyqxmd.com/read/29227247/stress-induced-cdk5-activity-enhances-cytoprotective-basal-autophagy-in-drosophila-melanogaster-by-phosphorylating-acinus-at-serine437
#10
Nilay Nandi, Lauren K Tyra, Drew Stenesen, Helmut Krämer
Cdk5 is a post-mitotic kinase with complex roles in maintaining neuronal health. The various mechanisms by which Cdk5 inhibits and promotes neurodegeneration are still poorly understood. Here, we show that in Drosophila melanogaster Cdk5 regulates basal autophagy, a key mechanism suppressing neurodegeneration. In a targeted screen, Cdk5 genetically interacted with Acinus (Acn), a primarily nuclear protein, which promotes starvation-independent, basal autophagy. Loss of Cdk5, or its required cofactor p35, reduces S437-Acn phosphorylation, whereas Cdk5 gain-of-function increases pS437-Acn levels...
December 11, 2017: ELife
https://www.readbyqxmd.com/read/29177651/measurement-of-chaperone-mediated-effects-on-polyglutamine-protein-aggregation-by-the-filter-trap-assay
#11
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/29172694/epigenetic-profiles-in-polyglutamine-disorders
#12
Hongmei Liu, Tie-Shan Tang, Caixia Guo
The dominant polyglutamine (polyQ) disorders are a group of progressive and incurable neurodegenerative disorders, which are caused by unstable expanded CAG trinucleotide repeats in the coding regions of their respective causative genes. The most prevalent polyQ disorders worldwide are Huntington's disease and spinocerebellar ataxia type 3. Epigenetic mechanisms, such as DNA methylation, histone modifications and chromatin remodeling and noncoding RNA regulation, regulate gene expression or genome function...
January 2018: Epigenomics
https://www.readbyqxmd.com/read/29172480/myricetin-reduces-toxic-level-of-cag-repeats-rna-in-huntington-s-disease-hd-and-spino-cerebellar-ataxia-scas
#13
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/29111377/mass-spectrometry-analyses-of-normal-and-polyglutamine-expanded-ataxin-3-reveal-novel-interaction-partners-involved-in-mitochondrial-function
#14
Line V Kristensen, Felix S Oppermann, Matthias J Rauen, Karina Fog, Thorsten Schmidt, Jana Schmidt, Tina Harmuth, Rasmus Hartmann-Petersen, Kenneth Thirstrup
Deubiquitinating enzymes (DUBs) play important roles in a variety of cellular processes, including regulation of protein homeostasis. The DUB ataxin-3 is an enzyme implicated in protein quality control mechanisms. In the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3), ataxin-3 contains an expanded polyglutamine (polyQ) stretch that leads to aggregation of the protein and neuronal dysfunction. Increasing the understanding of ataxin-3 protein interaction partners could help to elucidate disease mechanisms...
October 27, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29100804/immunohistochemical-localization-of-exoribonucleases-dis3l2-and-xrn1-in-intranuclear-inclusion-body-disease
#15
Fumiaki Mori, Kunikazu Tanji, Yasuo Miki, Yasuko Toyoshima, Hidenao Sasaki, Mari Yoshida, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
mRNA turnover controls gene expression under various conditions in aging and neurodegenerative diseases. Polyglutamine (polyQ) diseases and intranuclear inclusion body disease (INIBD) are neurodegenerative diseases characterized by the formation of nuclear inclusions. These inclusions are immunopositive for several proteins associated with amyotrophic lateral sclerosis. In amyotrophic lateral sclerosis, the processing of RNA from gene transcription through degradation (RNA metabolism) has been reported to be altered...
October 31, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29093475/hsp90-recognizes-the-n-terminus-of-huntingtin-involved-in-regulation-of-huntingtin-aggregation-by-usp19
#16
Wen-Tian He, Wei Xue, Yong-Guang Gao, Jun-Ye Hong, Hong-Wei Yue, Lei-Lei Jiang, Hong-Yu Hu
Huntington's disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract...
November 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29080331/optn-p-met468arg-and-atxn2-intermediate-length-polyq-extension-in-families-with-c9orf72-mediated-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#17
Sali M K Farhan, Tania F Gendron, Leonard Petrucelli, Robert A Hegele, Michael J Strong
We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS-FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment...
October 28, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/29066943/optimization-of-trans-splicing-for-huntington-s-disease-rna-therapy
#18
Hansjörg Rindt, Colton M Tom, Christian L Lorson, Virginia B Mattis
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon 1 of the Huntingtin (HTT) gene. We have previously demonstrated that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically reduce and repair mutant HTT (mtHTT). Here, the targeted tethering efficacy of the pre-mRNA trans-splicing modules (PTM) in HTT was optimized. Various PTMs that targeted the 3' end of HTT intron 1 or the intron 1 branch point were shown trans-splice into an HTT mini-gene, as well as the endogenous HTT pre-mRNA...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29056363/pramipexole-reduces-soluble-mutant-huntingtin-and-protects-striatal-neurons-through-dopamine-d3-receptors-in-a-genetic-model-of-huntington-s-disease
#19
Diego Luis-Ravelo, Héctor Estévez-Silva, Pedro Barroso-Chinea, Domingo Afonso-Oramas, Josmar Salas-Hernández, Julia Rodríguez-Núñez, Abraham Acevedo-Arozena, Daniel Marcellino, Tomás González-Hernández
Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD...
October 19, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29046994/peripheral-markers-of-autophagy-in-polyglutamine-diseases
#20
Giorgia Puorro, Angela Marsili, Francesca Sapone, Chiara Pane, Anna De Rosa, Peluso Silvio, Giuseppe De Michele, Alessandro Filla, Francesco Saccà
Polyglutamine disorders are neurodegenerative diseases that share a CAG repeat expansion in the coding region, resulting in aggregated proteins that can be only degraded through aggrephagy. We measured the expression of autophagy genes in peripheral blood mononuclear cells of 20 patients with Huntington's disease (HD), 20 with spinocerebellar ataxia type 2 (SCA2), and 20 healthy individuals. HD patients showed increased expression of MAP1LC3B (+ 43%; p = 0.048), SQSTM1 (+ 49%; p = 0.002), and WDFY3 (+ 89%; p < 0...
October 18, 2017: Neurological Sciences
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