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Spinocerebellar ataxia

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https://www.readbyqxmd.com/read/28934387/mutations-in-tgm6-induce-the-unfolded-protein-response-in-sca35
#1
Debasmita Tripathy, Beatrice Vignoli, Nandini Ramesh, Maria Jose Polanco, Marie Coutelier, Christopher D Stephen, Marco Canossa, Marie-Lorraine Monin, Pascale Aeschlimann, Shannon Turberville, Daniel Aeschlimann, Jeremy D Schmahmann, Marios Hadjivassiliou, Alexandra Durr, Udai B Pandey, Maria Pennuto, Manuela Basso
Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that the wild-type (TG6-WT) protein mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28923333/buccal-cell-micronucleus-frequency-is-significantly-elevated-in-patients-with-spinocerebellar-ataxia-type-2
#2
Dany A Cuello-Almarales, Luis E Almaguer-Mederos, Yaimé Vázquez-Mojena, Dennis Almaguer-Gotay, Pedro Zayas-Feria, José M Laffita-Mesa, Yanetza González-Zaldívar, Raúl Aguilera-Rodríguez, Annelié Rodríguez-Estupiñán, Luis Velázquez-Pérez
Spinocerebellar ataxia type 2 (SCA2) is part of a group of at least nine dominantly inherited disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving the expansion of a CAG repeat tract in coding regions of novel genes. Efforts have been made to identify biomarkers of disease progression, which would allow timely preventive therapeutic interventions. In the present study was assessed the influence of several genome instability biomarkers on SCA2 clinical severity...
April 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/28918024/antisense-oligonucleotide-mediated-removal-of-the-polyglutamine-repeat-in-spinocerebellar-ataxia-type-3-mice
#3
Lodewijk J A Toonen, Frank Rigo, Haico van Attikum, Willeke M C van Roon-Mom
Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegeneration. One important function of ataxin-3 is its involvement in the proteasomal protein degradation pathway, and long-term downregulation of the protein may therefore not be desirable. In the current study, we made use of antisense oligonucleotides to mask predicted exonic splicing signals, resulting in exon 10 skipping from ATXN3 pre-mRNA...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28918022/antisense-oligonucleotides-reduce-rna-foci-in-spinocerebellar-ataxia-36-patient-ipscs
#4
Kosuke Matsuzono, Keiko Imamura, Nagahisa Murakami, Kayoko Tsukita, Takuya Yamamoto, Yuishin Izumi, Ryuji Kaji, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Haruhisa Inoue
Spinocerebellar ataxia type 36 is a late-onset, slowly progressive cerebellar syndrome with motor neuron degeneration that is caused by expansions of a hexanucleotide repeat (GGCCTG) in the noncoding region of NOP56 gene, with a histopathological feature of RNA foci formation in postmortem tissues. Here, we report a cellular model using the spinocerebellar ataxia type 36 patient induced pluripotent stem cells (iPSCs). We generated iPSCs from spinocerebellar ataxia type 36 patients and differentiated them into neurons...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28912527/treatment-with-caffeic-acid-and-resveratrol-alleviates-oxidative-stress-induced-neurotoxicity-in-cell-and-drosophila-models-of-spinocerebellar-ataxia-type3
#5
Yu-Ling Wu, Jui-Chih Chang, Wei-Yong Lin, Chien-Chun Li, Mingli Hsieh, Haw-Wen Chen, Tsu-Shing Wang, Chin-San Liu, Kai-Li Liu
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death. Here we show that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro-oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3. Furthermore, CA and Res improved survival and locomotor activity and decreased mutant ataxin-3 and ROS levels in tBH-treated SCA3 Drosophila...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28905220/haplotype-study-in-sca10-families-provides-further-evidence-for-a-common-ancestral-origin-of-the-mutation
#6
Giovana B Bampi, Rafael Bisso-Machado, Tábita Hünemeier, Tailise C Gheno, Gabriel V Furtado, Diego Veliz-Otani, Mario Cornejo-Olivas, Pillar Mazzeti, Maria Cátira Bortolini, Laura B Jardim, Maria Luiza Saraiva-Pereira
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas...
September 13, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28904990/the-multiple-faces-of-spinocerebellar-ataxia-type-2
#7
REVIEW
Antonella Antenora, Carlo Rinaldi, Alessandro Roca, Chiara Pane, Maria Lieto, Francesco Saccà, Silvio Peluso, Giuseppe De Michele, Alessandro Filla
Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin-2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available...
September 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28900413/impaired-cerebellum-to-primary-motor-cortex-associative-plasticity-in-parkinson-s-disease-and-spinocerebellar-ataxia-type-3
#8
Ming-Kuei Lu, Jui-Cheng Chen, Chun-Ming Chen, Jeng-Ren Duann, Ulf Ziemann, Chon-Haw Tsai
BACKGROUND: Functional perturbation of the cerebellum (CB)-motor cortex (M1) interactions may underlie pathophysiology of movement disorders, such as Parkinson's disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently, M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on CB and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello-dentato-thalamo-cortical (CDTC) circuit...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28895081/novel-de-novo-kcnd3-mutation-in-a-japanese-patient-with-intellectual-disability-cerebellar-ataxia-myoclonus-and-dystonia
#9
Masanori Kurihara, Hiroyuki Ishiura, Takuya Sasaki, Juuri Otsuka, Toshihiro Hayashi, Yasuo Terao, Takashi Matsukawa, Jun Mitsui, Juntaro Kaneko, Kazutoshi Nishiyama, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Shimizu, Shoji Tsuji
Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c...
September 11, 2017: Cerebellum
https://www.readbyqxmd.com/read/28890930/parkinson-s-disease-associated-with-pure-atxn10-repeat-expansion
#10
Birgitt Schüle, Karen N McFarland, Kelsey Lee, Yu-Chih Tsai, Khanh-Dung Nguyen, Chao Sun, Mei Liu, Christie Byrne, Ramesh Gopi, Neng Huang, J William Langston, Tyson Clark, Francisco Javier Jiménez Gil, Tetsudo Ashizawa
Large, non-coding pentanucleotide repeat expansions of ATTCT in intron 9 of the ATXN10 gene typically cause progressive spinocerebellar ataxia with or without seizures and present neuropathologically with Purkinje cell loss resulting in symmetrical cerebellar atrophy. These ATXN10 repeat expansions can be interrupted by sequence motifs which have been attributed to seizures and are likely to act as genetic modifiers. We identified a Mexican kindred with multiple affected family members with ATXN10 expansions...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28887803/psychosis-in-spinocerebellar-ataxias-a-case-series-and-study-of-tyrosine-hydroxylase-in-substantia-nigra
#11
Katherine W Turk, Margaret E Flanagan, Samuel Josephson, C Dirk Keene, Suman Jayadev, Thomas D Bird
Spinocerebellar ataxias are a genetically heterogeneous group of degenerative diseases typically characterized by progressive ataxia and to various degrees, neuropathy, amyotrophy, and ocular abnormalities. There is increasing evidence for non-motor manifestations associated with cerebellar syndromes including cognitive and psychiatric features. We studied a retrospective clinical case series of eight subjects with spinocerebellar ataxias (SCAs) 2, 3, 7, and 17, all displaying features of psychosis, and also measured tyrosine hydroxylase (TH) staining of the substantia nigra (SN) at autopsy, among four of the subjects...
September 8, 2017: Cerebellum
https://www.readbyqxmd.com/read/28886343/dominant-mutations-in-grm1-cause-spinocerebellar-ataxia-type-44
#12
Lauren M Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B E Becker, Andrea H Németh
The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28877638/spinocerebellar-ataxia-a-critical-review-of-cognitive-and-socio-cognitive-deficits
#13
Flora Giocondo, Giuseppe Curcio
The primary aim of this contribution is to provide a critical discussion on cognitive and socio-cognitive implications of spinocerebellar ataxias (SCA) subtypes. The term SCA refers to a group of neurodegenerative disorders that have been increasingly investigated in the last years, sharing the characteristic of progressive ataxia resulting from degeneration of cerebellum and its connections. In past decades only involvement of cerebellum in behaviour and timing have been investigated, bringing to the belief about its central role in timing of movement and sensation, particularly for short intervals of time...
September 7, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/28855740/polyglutamine-spinocerebellar-ataxias-from-genes-to-potential-treatments
#14
REVIEW
Henry L Paulson, Vikram G Shakkottai, H Brent Clark, Harry T Orr
The dominantly inherited spinocerebellar ataxias (SCAs) are a large and diverse group of neurodegenerative diseases. The most prevalent SCAs (SCA1, SCA2, SCA3, SCA6 and SCA7) are caused by expansion of a glutamine-encoding CAG repeat in the affected gene. These SCAs represent a substantial portion of the polyglutamine neurodegenerative disorders and provide insight into this class of diseases as a whole. Recent years have seen considerable progress in deciphering the clinical, pathological, physiological and molecular aspects of the polyglutamine SCAs, with these advances establishing a solid base from which to pursue potential therapeutic approaches...
October 2017: Nature Reviews. Neuroscience
https://www.readbyqxmd.com/read/28854700/comparison-of-spinocerebellar-ataxia-type-3-mouse-models-identifies-early-gain-of-function-cell-autonomous-transcriptional-changes-in-oligodendrocytes
#15
Biswarathan Ramani, Bharat Panwar, Lauren R Moore, Bo Wang, Rogerio Huang, Yuanfang Guan, Henry L Paulson
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutamine diseases is the extent to which neurodegeneration is mediated through gain-of-function versus loss-of-function. To address this question in SCA3, we performed transcriptional profiling on the brainstem, a highly vulnerable brain region in SCA3, in a series of mouse models with varying degrees of ATXN3 expression and aggregation...
September 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28844804/dat-spect-may-have-diagnostic-value-in-prodromal-sca2-patients-with-parkinsonism
#16
Noriyuki Miyaue, Satoshi Tada, Rina Ando, Hirotaka Iwaki, Hayato Yabe, Noriko Nishikawa, Masahiro Nagai, Hiroshi Takashima, Masahiro Nomoto
INTRODUCTION: Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia. METHODS: (123)I-metaiodobenzyl guanidine ((123)I-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using (123)I-ioflupane ((123)I-FP-CIT) were performed for the six patients from three SCA2 families. RESULTS: (123)I-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested...
August 14, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28844644/role-of-corticotropin-releasing-factor-in-cerebellar-motor-control-and-ataxia
#17
Yi Wang, Zhang-Peng Chen, Qian-Xing Zhuang, Xiao-Yang Zhang, Hong-Zhao Li, Jian-Jun Wang, Jing-Ning Zhu
Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1-3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4-7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo-cerebellar system [10-14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia...
September 11, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28826917/missense-mutation-in-the-itpr1-gene-presenting-with-ataxic-cerebral-palsy-description-of-an-affected-family-and-literature-review
#18
Joyutpal Das, James Lilleker, Hannah Shereef, John Ealing
The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene on chromosome 3 belongs to a family of genes encoding intracellular calcium channel proteins. Such channels are located primarily within the endoplasmic reticular membrane and release Ca(2+), an intracellular messenger, which governs numerous intracellular and extracellular functions. We report a family with infantile-onset cerebellar ataxia with delayed motor development and intellectual disability caused by a heterozygous c.805C>T, p.Arg269Trp missense mutation in ITPR1...
July 8, 2017: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/28821675/synergistic-toxicity-of-polyglutamine-expanded-tbp-in-glia-and-neuronal-cells-therapeutic-implications-for-sca17
#19
Yang Yang, Su Yang, Jifeng Guo, Yiting Cui, Baisha Tang, Xiao-Jiang Li, Shihua Li
Spinocerebellar ataxia 17 (SCA17) is caused by polyglutamine (polyQ) repeat expansion in the TATA-binding protein (TBP) and is among a family of neurodegenerative diseases in which polyQ expansion leads to preferential neuronal loss in the brain. Although previous studies have demonstrated that expression of polyQ-expanded proteins in glial cells can cause neuronal injury via non-cell-autonomous mechanisms, these studies investigated animal models that overexpress transgenic mutant proteins. Since glial cells are particularly reactive to overexpressed mutant proteins, it is important to investigate the in vivo role of glial dysfunction in neurodegeneration when mutant polyQ proteins are endogenously expressed...
August 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28819076/-molecularly-targeted-therapy-of-spinocerebellar-ataxia-type-1-by-hmgb1
#20
Kyota Fujita, Hitoshi Okazawa
Spinocerebellar ataxia type 1 (SCA1) is an untreatable neurodegenerative disease. We reported a decrease in HMGB1 levels in the nucleus of cerebellar neurons in mouse SCA 1. The decrease in this DNA architectural protein leads to the impairment of DNA repair and transcription, the two essential nuclear functions, and eventually causes neurodegeneration. We have designed a gene therapy using AAV-HMGB1 and tested it using the mouse model. Based on the results of these proof of concept (POC) studies, we are now preparing GMP-level AAV vector and designing human clinical trials...
August 2017: Brain and Nerve, Shinkei Kenkyū No Shinpo
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