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https://www.readbyqxmd.com/read/27896316/compound-heterozygous-intermediate-mjd-alleles-cause-cerebellar-ataxia-with-sensory-neuropathy
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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/27759814/itaja%C3%A3-santa-catarina-azorean-ancestry-and-spinocerebellar-ataxia-type-3
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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...
August 16, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27570389/spinocerebellar-ataxia-type-6-in-eastern-india-some-new-observations
#13
Kalyan B Bhattacharyya, Debabrata Pulai, Deb Shankar Guin, Goutam Ganguly, Anindita Joardar, Sarnava Roy, Saurabh Rai, Atanu Biswas, Alok Pandit, Arijit Roy, Asit Kumar Senapati
INTRODUCTION: Spinocerebellar ataxias (SCAs) are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG) repeat. The global prevalence of SCA is 0...
July 2016: Annals of Indian Academy of Neurology
https://www.readbyqxmd.com/read/27491321/phonoarticulation-in-spinocerebellar-ataxia-type-3
#14
A E Wolf, L Mourão, M C Jr França, A J Machado Júnior, A N Crespo
Phonoarticulation is characterized by changes in resonance, diadochokinesis, prosody, sound frequency, vocal quality, and intraoral pressure. The main aim of this study was to characterize the phonoarticulation in spinocerebellar ataxia type 3 (SCA3) and correlate it with clinical and genetic factors. Thirty-one patients with SCA3 who were subjected to spontaneous speech recordings and phonoarticulatory diadochokinesis (DDK) participated in the study. Speech analyses were performed starting after 10 s of spontaneous speech, by three experienced speech therapists, using a protocol for dysarthria adapted from the Mayo Clinic...
August 4, 2016: European Archives of Oto-rhino-laryngology
https://www.readbyqxmd.com/read/27469193/far-infrared-radiation-protects-viability-in-a-cell-model-of-spinocerebellar-ataxia-by-preventing-polyq-protein-accumulation-and-improving-mitochondrial-function
#15
Jui-Chih Chang, Shey-Lin Wu, Fredrik Hoel, Yu-Shan Cheng, Ko-Hung Liu, Mingli Hsieh, August Hoel, Karl Johan Tronstad, Kuo-Chia Yan, Ching-Liang Hsieh, Wei-Yong Lin, Shou-Jen Kuo, Shih-Li Su, Chin-San Liu
Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27392837/vestibulo-ocular-reflex-dynamics-with%C3%A2-head-impulses-discriminates-spinocerebellar-ataxias-types-1-2-and-3-and%C3%A2-friedreich-ataxia
#16
L Luis, J Costa, E Muñoz, M de Carvalho, S Carmona, E Schneider, C R Gordon, J Valls-Solé
OBJECTIVE: Although the diagnosis of inherited ataxias is ultimately genetic, this usually means an extensive and expensive process. This justifies the search for distinct clinical signs that may potentially help orient molecular diagnosis. METHODS: We explored the vestibulo-ocular reflex (VOR) with the video Head Impulse Test in patients diagnosed with spinocerebellar ataxia (SCA) type 3 (n = 15), type 1 (n = 4) and type 2 (n = 4), Friedreich's ataxia (FA) (n = 9) and healthy controls (n = 40)...
July 2, 2016: Journal of Vestibular Research: Equilibrium & Orientation
https://www.readbyqxmd.com/read/27377427/on-the-distribution-of-intranuclear-and-cytoplasmic-aggregates-in-the-brainstem-of-patients-with-spinocerebellar-ataxia-type-2-and-3
#17
Kay Seidel, Sonny Siswanto, Michaela Fredrich, Mohamed Bouzrou, Wilfred F A den Dunnen, Inci Özerden, Horst-Werner Korf, Bela Melegh, Jeroen J de Vries, Ewout R Brunt, Georg Auburger, Udo Rüb
The polyglutamine (polyQ) diseases are a group of genetically and clinically heterogeneous neurodegenerative diseases, characterized by the expansion of polyQ sequences in unrelated disease proteins, which form different types of neuronal aggregates. The aim of this study was to characterise the aggregation pathology in the brainstem of spinocerebellar ataxia type 2 (SCA2) and 3 (SCA3) patients. For good recognition of neurodegeneration and rare aggregates, we employed 100 µm PEG embedded brainstem sections, which were immunostained with the 1C2 antibody, targeted at polyQ expansions, or with an antibody against p62, a reliable marker of protein aggregates...
July 5, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27346191/generation-of-spinocerebellar-ataxia-type-3-patient-derived-induced-pluripotent-stem-cell-line-sca3-b11
#18
Susanne K Hansen, Helena Borland, Lis F Hasholt, Zeynep Tümer, Jørgen E Nielsen, Mikkel A Rasmussen, Troels T Nielsen, Tina C Stummann, Karina Fog, Poul Hyttel
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by an expansion of the CAG-repeat in ATXN3. In this study, induced pluripotent stem cells (iPSCs) were generated from SCA3 patient dermal fibroblasts by electroporation with episomal plasmids encoding L-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation...
May 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27346190/generation-of-spinocerebellar-ataxia-type-3-patient-derived-induced-pluripotent-stem-cell-line-sca3-a11
#19
Susanne K Hansen, Helena Borland, Lis F Hasholt, Zeynep Tümer, Jørgen E Nielsen, Mikkel A Rasmussen, Troels T Nielsen, Tina C Stummann, Karina Fog, Poul Hyttel
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG-repeat expanding mutation in ATXN3. We generated induced pluripotent stem cells (iPSCs) from a SCA3 patient by electroporation of dermal fibroblasts with episomal plasmids encoding L-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation...
May 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27333979/a-longitudinal-investigation-into-cognition-and-disease-progression-in-spinocerebellar-ataxia-types-1-2-3-6-and-7
#20
Amy Moriarty, Arron Cook, Helen Hunt, Matthew E Adams, Lisa Cipolotti, Paola Giunti
BACKGROUND: The natural history of clinical symptoms in the spinocerebellar ataxias (SCA)s has been well characterised. However there is little longitudinal data comparing cognitive changes in the most common SCA subtypes over time. The present study provides a preliminary longitudinal characterisation of the clinical and cognitive profiles in patients with SCA1, SCA2, SCA3, SCA6 and SCA7, with the aim of elucidating the role of the cerebellum in cognition. METHODS: 13 patients with different SCAs all caused by CAG repeat expansion (SCA1, n = 2; SCA2, n = 2; SCA3, n = 2; SCA6, n = 4; and SCA7, n = 3) completed a comprehensive battery of cognitive and mood assessments at two time points, a mean of 7...
2016: Orphanet Journal of Rare Diseases
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