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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
João Valente Duarte, Ricardo Faustino, Mercês Lobo, Gil Cunha, César Nunes, Carlos Ferreira, Cristina Januário, Miguel Castelo-Branco
Machado-Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry...
October 2016: Human Brain Mapping
Mafalda Raposo, Conceição Bettencourt, Amanda Ramos, Nadiya Kazachkova, João Vasconcelos, Teresa Kay, Jácome Bruges-Armas, Manuela Lima
Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1A, IL1B, IL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR...
May 31, 2016: Neuromolecular Medicine
Wioletta Krysa, Anna Sulek, Maria Rakowicz, Walentyna Szirkowiec, Jacek Zaremba
Spinocerebellar ataxias (SCAs) have irregular distributions worldwide. SCA1 is the most frequent in Poland, and no cases of SCA3 of Polish origin has yet been identified. In view of such patterns of SCAs occurrence, the relative frequency, geographical distribution and a possible founder effect of SCA1 were investigated. DNA samples of 134 probands with SCA1 and 228 controls were analysed. The genotyping of four markers, D6S89, D6S109, D6S274, D6S288, around the ATXN1 gene (SCA1) and sequencing of the selected variant of D6S89 were performed...
August 2016: Neurological Sciences
A Klaes, E Reckziegel, M C Franca, T J R Rezende, L M Vedolin, L B Jardim, J A Saute
BACKGROUND AND PURPOSE: Polyglutamine expansion spinocerebellar ataxias are autosomal dominant slowly progressive neurodegenerative diseases with no current treatment. MR imaging is the best-studied surrogate biomarker candidate for polyglutamine expansion spinocerebellar ataxias, though with conflicting results. We aimed to review quantitative central nervous system MR imaging technique findings in patients with polyglutamine expansion spinocerebellar ataxias and correlations with well-established clinical and molecular disease markers...
August 2016: AJNR. American Journal of Neuroradiology
Norie Ito, Kenjiro Kamiguchi, Katsuya Nakanishi, Alice Sokolovskya, Yoshihiko Hirohashi, Yasuaki Tamura, Aiko Murai, Eri Yamamoto, Takayuki Kanaseki, Tomohide Tsukahara, Vitaly Kochin, Susumu Chiba, Shun Shimohama, Noriyuki Sato, Toshihiko Torigoe
Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus...
June 10, 2016: Biochemical and Biophysical Research Communications
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