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https://www.readbyqxmd.com/read/28223212/n-butylidenephthalide-exhibits-protection-against-neurotoxicity-through-regulation-of-tryptophan-2-3-dioxygenase-in-spinocerebellar-ataxia-type-3
#1
Karthyayani Rajamani, Jen-Wei Liu, Cheng-Han Wu, I-Tsang Chiang, Deng-Huwei You, Si-Yin Lin, Dean-Kuo Hsieh, Shinn-Zong Lin, Horng-Jyh Harn, Tzyy-Wen Chiou
Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is characterized by the repetition of a CAG codon in the ataxin-3 gene (ATXN3), which leads to the formation of an elongated mutant ATXN3 protein that can neither be denatured nor undergo proteolysis in the normal manner. This abnormal proteolysis leads to the accumulation of cleaved fragments, which have been identified as toxic and further they act as a seed for more aggregate formation, thereby increasing toxicity in neuronal cells. To date, there have been few studies or treatment strategies that have focused on controlling toxic fragment formation...
February 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28195427/oculomotor-deficits-in-spinocerebellar-ataxia-type-3-potential-biomarkers-of-preclinical-detection-and-disease-progression
#2
Chao Wu, Ding-Bang Chen, Li Feng, Xiang-Xue Zhou, Ji-Wei Zhang, Hua-Jing You, Xiu-Ling Liang, Zhong Pei, Xun-Hua Li
AIMS: To detect specific oculomotor deficits in preclinical stage of spinocerebellar ataxia type 3 (SCA3) and evaluate whether these abnormalities prove useful as potential biomarkers of disease progression. METHODS: A Chinese cohort of 56 patients with SCA3, including 12 preclinical carriers of SCA3 (pre-SCA3) and 44 manifest SCA3, and 26 healthy control individuals were recruited. We performed a detailed investigation on central oculomotor performance including fixation, gaze, smooth pursuit, prosaccade, and antisaccade using video-oculography...
February 13, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28103906/thermodynamic-and-kinetic-stability-of-the-josephin-domain-closed-arrangement-evidences-from-replica-exchange-molecular-dynamics
#3
Gianvito Grasso, Jack A Tuszynski, Umberto Morbiducci, Ginevra Licandro, Andrea Danani, Marco A Deriu
BACKGROUND: Molecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure...
January 19, 2017: Biology Direct
https://www.readbyqxmd.com/read/28094059/alteration-of-methylation-status-in-the-atxn3-gene-promoter-region-is-linked-to-the-sca3-mjd
#4
Chunrong Wang, Huirong Peng, Jiada Li, Dongxue Ding, Zhao Chen, Zhe Long, Yun Peng, Xin Zhou, Wei Ye, Kai Li, Qian Xu, Sanxi Ai, Chengyuan Song, Ling Weng, Rong Qiu, Kun Xia, Beisha Tang, Hong Jiang
DNA methylation has been acknowledged as one of the key epigenetic mechanisms involved in the regulation of gene expression and genomic functions. Alteration of the DNA methylation level has been linked to modification of the disease progression and instability regulation of certain disease-causing repeats in neurodegenerative diseases. In this study, blood samples collected from spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) patients versus control were used to explore the potential link of DNA methylation levels at ATXN3 gene promoter to the pathogenesis of SCA3/MJD...
December 24, 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/28065793/polyglutamine-expansion-of-ataxin-3-alters-its-degree-of-ubiquitination-and-phosphorylation-at-specific-sites
#5
Line V Kristensen, Felix S Oppermann, Matthias J Rauen, Rasmus Hartmann-Petersen, Kenneth Thirstrup
Ubiquitination and phosphorylation of proteins represent post translational modifications (PTMs) capable of regulating a variety of cellular processes. In the neurodegenerative disorder spinocerebellar ataxia type 3 (SCA3), the disease causing protein ataxin-3 carries an expanded polyglutamine (polyQ) stretch causing it to aggregate in nuclear inclusions. These inclusions are decorated with ubiquitin suggestive of a malfunction in the clearance of the mutant protein. Differences in ubiquitin chain topology between normal and polyQ expanded ataxin-3 could be involved in the differential clearance of the two proteins and play a role in SCA3 pathogenesis...
January 6, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28042641/progression-of-dysphagia-in-spinocerebellar-ataxia-type-6
#6
Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi Ueno, Susumu Kusunoki, Yusaku Nakamura
Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant triplet repeat disease, predominantly affects the cerebellum with a late onset and generally good prognosis. Dysphagia is commonly associated with the outcomes of neurodegenerative diseases such as SCA6. Although the characteristics of dysphagia have been rarely reported in SCA6, our previous study indicated that dysphagia is generally milder in SCA6 than in SCA3, another inherited ataxia with multisystem involvement. However, abnormalities in the pharyngeal phase in SCA6 were indistinguishable from those in SCA3, with no explainable reason...
January 2, 2017: Dysphagia
https://www.readbyqxmd.com/read/27942452/cag-repeat-length-does-not-associate-with-the-rate-of-cerebellar-degeneration-in-spinocerebellar-ataxia-type-3
#7
Shang-Ran Huang, Yu-Te Wu, Chii-Wen Jao, Bing-Wen Soong, Jiing-Feng Lirng, Hsiu-Mei Wu, Po-Shan Wang
This cross-sectional study investigated the correlation between the CAG repeat length and the degeneration of cerebellum in spinocerebellar ataxia type 3 (SCA3) patients based on neuroimaging approaches. Forty SCA3 patients were recruited and classified into two subgroups according to their CAG repeat lengths (≥ 74 and < 74). We measured each patient's Scale for the Assessment and Rating of Ataxia (SARA) score, N-acetylaspartate (NAA)/creatine (Cr) ratios based on magnetic resonance spectroscopy (MRS), and 3-dimensional fractal dimension (3D-FD) values derived from magnetic resonance imaging (MRI) results...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/27934588/generation-of-human-embryonic-stem-cell-line-chhes-472-from-abnormal-embryos-diagnosed-with-spinocerebellar-ataxia-type-3
#8
Lvjun Liu, Sicong Zeng, Yi Sun, Xiaoying Zhou, Jing Chen, Juan Du, Guangxiu Lu, Ge Lin, Qi Ouyang
Spinocerebellar ataxia type3 (SCA3) is an autosomal dominant neurodegenerative disorder. Human embryonic stem cell line chHES-472 was derived from abnormal embryo donated by SCA3 patient after preimplantation genetic diagnosis (PGD) treatment. This cell line had a normal karyotype and retained the disease-causing mutant in ATXN3 gene. Characteristic tests proved that the embryonic stem cell line presented typical markers of pluripotency and had the capability to form the three germlayers in vivo.
October 24, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27896316/compound-heterozygous-intermediate-mjd-alleles-cause-cerebellar-ataxia-with-sensory-neuropathy
#9
Yuji Takahashi, Masahiro Kanai, Tomoya Taminato, Shoko Watanabe, Chihiro Matsumoto, Toshiyuki Araki, Tomoko Okamoto, Masafumi Ogawa, Miho Murata
Spinocerebellar degeneration (SCD) is a group of disorders characterized by progressive ataxia caused by dysfunction and atrophy of the cerebellum or its projections. Approximately one-third of SCD cases are familial SCD, the majority of which are attributed to CAG triplet repeat expansions including spinocerebellar ataxia (SCA)1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA6, SCA8, SCA12, SCA17, and dentate-rubro-pallido-luysian atrophy (DRPLA). The triplet repeat number of the alleles representing complete penetrance varies among diseases...
February 2016: Neurology. Genetics
https://www.readbyqxmd.com/read/27878228/lithium-carbonate-and-coenzyme-q10-reduce-cell-death-in-a-cell-model-of-machado-joseph-disease
#10
C M Lopes-Ramos, T C Pereira, D B Dogini, R Gilioli, I Lopes-Cendes
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture...
November 21, 2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/27851749/the-machado-joseph-disease-deubiquitinase-ataxin-3-regulates-the-stability-and-apoptotic-function-of-p53
#11
Hongmei Liu, Xiaoling Li, Guozhu Ning, Shu Zhu, Xiaolu Ma, Xiuli Liu, Chunying Liu, Min Huang, Ina Schmitt, Ullrich Wüllner, Yamei Niu, Caixia Guo, Qiang Wang, Tie-Shan Tang
As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish...
November 2016: PLoS Biology
https://www.readbyqxmd.com/read/27848087/the-initial-symptom-and-motor-progression-in-spinocerebellar-ataxias
#12
Lan Luo, Jie Wang, Raymond Y Lo, Karla P Figueroa, Stefan M Pulst, Pei-Hsin Kuo, Susan Perlman, George Wilmot, Christopher M Gomez, Jeremy D Schmahmann, Henry Paulson, Vikram G Shakkottai, Sarah H Ying, Theresa Zesiewicz, Khalaf Bushara, Michael Geschwind, Guangbin Xia, S H Subramony, Tetsuo Ashizawa, Sheng-Han Kuo
The aim of this study is to determine whether the initial symptom associates with motor progression in spinocerebellar ataxias (SCAs). SCAs are clinically heterogeneous and the initial presentation may represent different subtypes of SCA with different motor progression. We studied 317 participants with SCAs1, 2, 3, and 6 from the Clinical Research Consortium for SCAs (CRC-SCA) and repeatedly measured the severity of ataxia for 2 years. SCA patients were divided into gait-onset and non-gait-onset (speech, vision, and hand dexterity) groups based on the initial presentation...
November 15, 2016: Cerebellum
https://www.readbyqxmd.com/read/27847820/autophagy-promoted-the-degradation-of-mutant-atxn3-in-neurally-differentiated-spinocerebellar-ataxia-3-human-induced-pluripotent-stem-cells
#13
Zhanhui Ou, Min Luo, Xiaohua Niu, Yuchang Chen, Yingjun Xie, Wenyin He, Bing Song, Yexing Xian, Di Fan, Shuming OuYang, Xiaofang Sun
Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autophagy in neurodegenerative disorders, including SCA3, using transfection models with expression of pathogenic proteins in normal cells. In the current study, we aimed to develop an improved model for studying SCA3 in vitro using patient-derived cells...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27770571/silencing-of-genes-responsible-for-polyq-diseases-using-chemically-modified-single-stranded-sirnas
#14
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...
2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27759814/itaja%C3%A3-santa-catarina-azorean-ancestry-and-spinocerebellar-ataxia-type-3
#15
Hélio A G Teive, Adriana Moro, Walter O Arruda, Salmo Raskin, Gladys M G Teive, Norberto Dalabrida, Renato P Munhoz
The authors present a historical review of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the most common form of spinocerebellar ataxia in Brazil, and consider the high frequency of cases in families from Itajaí, a city on the coast of the state of Santa Catarina with a large population of Portuguese/Azorean descent.
October 2016: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/27731380/antisense-oligonucleotide-mediated-exon-skipping-as-a-strategy-to-reduce-proteolytic-cleavage-of-ataxin-3
#16
Lodewijk J A Toonen, Iris Schmidt, Martijn S Luijsterburg, Haico van Attikum, Willeke M C van Roon-Mom
Spinocerebellar ataxia type-3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in the ataxin-3 protein. Cleavage of mutant ataxin-3 by proteolytic enzymes yields ataxin-3 fragments containing the polyglutamine stretch. These shorter ataxin-3 fragments are thought to be involved in SCA3 pathogenesis due to their increased cellular toxicity and their involvement in formation of the characteristic neuronal aggregates. As a strategy to prevent formation of toxic cleavage fragments, we investigated an antisense oligonucleotide-mediated modification of the ataxin-3 pre-mRNA through exon skipping of exon 8 and 9, resulting in the removal of a central 88 amino acid region of the ataxin-3 protein...
October 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27689815/motor-cortical-dysfunction-develops-in-spinocerebellar-ataxia-type-3
#17
Michelle A Farrar, Steve Vucic, Garth Nicholson, Matthew C Kiernan
OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by cerebellar ataxia and variable expression of clinical features beyond the cerebellum. To gain further insights into disease pathophysiology, the present study explored motor cortex function in SCA3 to determine whether cortical dysfunction was present and if this contributed to the development of clinical manifestations. METHODS: Clinical phenotyping and longitudinal assessments were combined with central (threshold-tracking transcranial magnetic stimulation) and peripheral (nerve excitability) techniques in 11 genetically characterized SCA3 patients...
September 15, 2016: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/27647319/triplet-repeat-primed-pcr-tp-pcr-in-molecular-diagnostic-testing-for-spinocerebellar-ataxia-type-3-sca3
#18
Ana Rosa Vieira Melo, Amanda Ramos, Nadiya Kazachkova, Mafalda Raposo, Bruno Filipe Bettencourt, Ana Rita Rendeiro, Teresa Kay, João Vasconcelos, Jácome Bruges-Armas, Manuela Lima
INTRODUCTION AND OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder for which the routine molecular testing is based on PCR and automated capillary electrophoresis. When only a normal allele is detected by standard PCR, the hypothesis of a failed amplification of the expanded allele must be raised. In such cases, complementary techniques such as Southern Blot or triplet repeat primed PCR (TP-PCR) have to be applied. For SCA3, TP-PCR is implemented in some diagnostic laboratories, but a tested protocol has yet to be published...
September 20, 2016: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/27600091/clinical-features-and-genetic-diagnosis-of-hereditary-spinocerebellar-ataxia-3
#19
Yaoguang Wang, Xiaokai Yang, Weide Ma, Jinxin Li, Qingyuan Zhang, Shuqi Xia, Hai Wang, Chenghui Zhang, Xiaomin Xu, Jiayong Zheng
Spinocerebellar ataxia type 3 (SCA3) is a rare inherited autosomal dominant progressive neurological disorder, which results from a CAG‑repeat expansion in the gene encoding the deubiquitinating enzyme, ataxin‑3. At present, no effective treatment is available for this fatal disorder; however, certain studies have suggested that reducing the levels of mutant ataxin‑3 protein may reverse or halt the progression of disease in patients with SCA3. In the present study, clinical examinations were performed on a patient with SCA3 who exhibited disease features including coughing, expectoration and was bedridden with mobility limitation...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27596958/induced-pluripotent-stem-cell-derived-neurons-for-the-study-of-spinocerebellar-ataxia-type-3
#20
Susanne K Hansen, Tina C Stummann, Helena Borland, Lis F Hasholt, Zeynep Tümer, Jørgen E Nielsen, Mikkel A Rasmussen, Troels T Nielsen, Justus C A Daechsel, Karina Fog, Poul Hyttel
The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC) lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method and the resulting SCA3 iPSCs were differentiated into neurons. These neuronal lines harbored the disease causing mutation, expressed comparable levels of several neuronal markers and responded to the neurotransmitters, glutamate/glycine, GABA and acetylcholine...
September 2016: Stem Cell Research
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