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Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model  [PDF]
Kei Watase,Jennifer R Gatchel,Yaling Sun,Effat Emamian,Richard Atkinson,Ronald Richman,Hidehiro Mizusawa,Harry T Orr,Chad Shaw,Huda Y Zoghbi
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040182
Abstract: Background Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease. Methods and Findings Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity. Conclusions The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.
The SCA1 (Spinocerebellar ataxia type 1) and MJD (Machado-Joseph disease) CAG repeats in normal individuals: segregation analysis and allele frequencies
Wiezel, Cláudia Emília Vieira;Canas, Maria do Carmo Tomit?o;Sim?es, Aguinaldo Luiz;
Genetics and Molecular Biology , 2003, DOI: 10.1590/S1415-47572003000200002
Abstract: spinocerebellar ataxia type 1 (sca1) and machado-joseph disease (mjd/sca3) are autosomal dominant neurodegenerative diseases caused by expansions of a cag trinucleotide repeat in the sca1 and mjd genes. these expanded sequences are unstable upon transmission, leading to an intergeneration increase in the number of repeats (dynamic mutation). the transmission of the cag repeat was studied in normal mother-father-child trios, referred for paternity testing (sca1, n = 367; mjd, n = 879). no segregation distortion was detected. the cag allele frequencies were determined in 330 unrelated individuals (fathers from couples tested for paternity). the allele frequency distributions did not differ from those previously reported for european populations. the estimated values for the statistic parameters indicating diversity at the sca1 locus did not differ much from those reported previously for other strs in the brazilian population, while those for the mjd locus were close to or higher than the maximum values of previous reports. this shows that sca1 and mjd are highly informative loci for applications in genetic and population studies and for forensic analysis.
The SCA1 (Spinocerebellar ataxia type 1) and MJD (Machado-Joseph disease) CAG repeats in normal individuals: segregation analysis and allele frequencies  [cached]
Wiezel Cláudia Emília Vieira,Canas Maria do Carmo Tomit?o,Sim?es Aguinaldo Luiz
Genetics and Molecular Biology , 2003,
Abstract: Spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD/SCA3) are autosomal dominant neurodegenerative diseases caused by expansions of a CAG trinucleotide repeat in the SCA1 and MJD genes. These expanded sequences are unstable upon transmission, leading to an intergeneration increase in the number of repeats (dynamic mutation). The transmission of the CAG repeat was studied in normal mother-father-child trios, referred for paternity testing (SCA1, n = 367; MJD, n = 879). No segregation distortion was detected. The CAG allele frequencies were determined in 330 unrelated individuals (fathers from couples tested for paternity). The allele frequency distributions did not differ from those previously reported for European populations. The estimated values for the statistic parameters indicating diversity at the SCA1 locus did not differ much from those reported previously for other STRs in the Brazilian population, while those for the MJD locus were close to or higher than the maximum values of previous reports. This shows that SCA1 and MJD are highly informative loci for applications in genetic and population studies and for forensic analysis.
Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients
Lopes-Cendesi, Iscia;Teive, Hélio G.A.;Calcagnotto, Maria E;da Costa, Jaderson C.;Cardoso, Francisco;Viana, Erika;Maciel, Jaime A.;Radvany, Jo?o;Arruda, Walter O.;Trevisol-Bittencourt, Paulo C.;Rosa Neto, Pedro;Silveira, Isabel;Steiner, Carlos E.;Pinto-Júnior, Walter;Santos, André S.;Correa Neto, Ylmar;Werneck, Lineu C.;Araújo, Abelardo Q.C.;Carakushansky, Gerson;Mello, Luiz R.;Jardim, Laura B.;Rouleau, Guy A.;
Arquivos de Neuro-Psiquiatria , 1997, DOI: 10.1590/S0004-282X1997000400001
Abstract: spinocerebellar ataxia type 1 (sca1), spinocerebellar ataxia type 2 (sca2) and machado-joseph disease or spinocerebellar ataxia type 3 (mjd/sca3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (sca) caused by expansions of an unstable cag repeat localized in the coding region of the causative genes. another related disease, dentatorubropallidoluysian atrophy (drpla) is also caused by an unstable triplet repeat and can present as sca in late onset patients. we investigated the frequency of the sca1, sca2, mjd/sca3 and drpla mutations in 328 brazilian patients with sca, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of brazil. we found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. the frequency of the sca1 mutation was 3% of all patients; and 6 % in the dominantly inherited scas. we identified the sca2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. the mjd/sca3 mutation was detected in 30 % of all patients; and in the 44% of the dominantly inherited cases. we found no drpla mutation. in addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of brazil. these results suggest that sca may be occasionally caused by the sca1 and sca2 mutations in the brazilian population, and that the mjd/sca3 mutation is the most common cause of dominantly inherited sca in brazil.
The Role of Interruptions in polyQ in the Pathology of SCA1  [PDF]
Rajesh P. Menon equal contributor,Suran Nethisinghe equal contributor,Serena Faggiano,Tommaso Vannocci,Human Rezaei,Sally Pemble,Mary G. Sweeney,Nicholas W. Wood,Mary B. Davis,Annalisa Pastore ,Paola Giunti
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003648
Abstract: At least nine dominant neurodegenerative diseases are caused by expansion of CAG repeats in coding regions of specific genes that result in abnormal elongation of polyglutamine (polyQ) tracts in the corresponding gene products. When above a threshold that is specific for each disease the expanded polyQ repeats promote protein aggregation, misfolding and neuronal cell death. The length of the polyQ tract inversely correlates with the age at disease onset. It has been observed that interruption of the CAG tract by silent (CAA) or missense (CAT) mutations may strongly modulate the effect of the expansion and delay the onset age. We have carried out an extensive study in which we have complemented DNA sequence determination with cellular and biophysical models. By sequencing cloned normal and expanded SCA1 alleles taken from our cohort of ataxia patients we have determined sequence variations not detected by allele sizing and observed for the first time that repeat instability can occur even in the presence of CAG interruptions. We show that histidine interrupted pathogenic alleles occur with relatively high frequency (11%) and that the age at onset inversely correlates linearly with the longer uninterrupted CAG stretch. This could be reproduced in a cellular model to support the hypothesis of a linear behaviour of polyQ. We clarified by in vitro studies the mechanism by which polyQ interruption slows down aggregation. Our study contributes to the understanding of the role of polyQ interruption in the SCA1 phenotype with regards to age at disease onset, prognosis and transmission.
Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs  [PDF]
Jeonghyeon Park, Keumhan Noh, Hae Won Lee, Mi-sun Lim, Sook Jin Seong, Jeong Ju Seo, Eun-Jung Kim, Wonku Kang, Young-Ran Yoon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060556
Abstract: Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography–mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5′-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
Glial S100B Positive Vacuoles In Purkinje Cells: Earliest Morphological Abnormality In SCA1 Transgenic Mice  [cached]
Parminder J.S. VIG,Maripar E. LOPEZ,Jinrong WEI,David R. D'SOUZA
Journal of Neurological Sciences , 2006,
Abstract: Spinocerebellar ataxia-1 (SCA1) is caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-1. The overexpression of mutant ataxin-1 in SCA1 transgenic mice results in the formation of cytoplasmic vacuoles in Purkinje neurons (PKN) of the cerebellum. PKN are closely associated with neighboring Bergmann glia. To elucidate the role of Bergmann glia in SCA1 pathogenesis, cerebellar tissue from 7 days to 6 wks old SCA1 transgenic and wildtype mice were used. We observed that Bergmann glial S100B protein is localized to the cytoplasmic vacuoles in SCA1 PKN. These S100B positive cytoplasmic vacuoles began appearing much before the onset of behavioral abnormalities, and were negative for other glial and PKN marker proteins. Electron micrographs revealed that vacuoles have a double membrane. In the vacuoles, S100B colocalized with receptors of advanced glycation end-products (RAGE), and S100B co-immunoprecipated with cerebellar RAGE. In SCA1 PKN cultures, exogenous S100B protein interacted with the PKN membranes and was internalized. These data suggest that glial S100B though extrinsic to PKN is sequestered into cytoplasmic vacuoles in SCA1 mice at early postnatal ages. Further, S100B may be binding to RAGE on Purkinje cell membranes before these membranes are internalized.
Partial Loss of Ataxin-1 Function Contributes to Transcriptional Dysregulation in Spinocerebellar Ataxia Type 1 Pathogenesis  [PDF]
Juan Crespo-Barreto,John D. Fryer,Chad A. Shaw,Harry T. Orr,Huda Y. Zoghbi
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001021
Abstract: Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1). Molecular and genetic data indicate that SCA1 is mainly caused by a gain-of-function mechanism. However, deletion of wild-type ATXN1 enhances SCA1 pathogenesis, whereas increased levels of an evolutionarily conserved paralog of ATXN1, Ataxin 1-Like, ameliorate it. These data suggest that a partial loss of ATXN1 function contributes to SCA1. To address this possibility, we set out to determine if the SCA1 disease model (Atxn1154Q/+ mice) and the loss of Atxn1 function model (Atxn1?/? mice) share molecular changes that could potentially contribute to SCA1 pathogenesis. To identify transcriptional changes that might result from loss of function of ATXN1 in SCA1, we performed gene expression microarray studies on cerebellar RNA from Atxn1?/? and Atxn1154Q/+ cerebella and uncovered shared gene expression changes. We further show that mild overexpression of Ataxin-1-Like rescues several of the molecular and behavioral defects in Atxn1?/? mice. These results support a model in which Ataxin 1-Like overexpression represses SCA1 pathogenesis by compensating for a partial loss of function of Atxn1. Altogether, these data provide evidence that partial loss of Atxn1 function contributes to SCA1 pathogenesis and raise the possibility that loss-of-function mechanisms contribute to other dominantly inherited neurodegenerative diseases.
Temporal Retinal Nerve Fiber Loss in Patients with Spinocerebellar Ataxia Type 1  [PDF]
Sarah Stricker, Timm Oberwahrenbrock, Hanna Zimmermann, Jan Schroeter, Matthias Endres, Alexander U. Brandt, Friedemann Paul
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023024
Abstract: Background Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement. Objective To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls. Methodology/Principal Findings Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT) compared to healthy controls (84±13 μm vs. 97±8 μm, p = 0.004). Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005) whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm3 vs. 8.61±0.41 mm3, p = 0.15). Conclusion In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON) or dominant optic atrophy (DOA).
Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1
Lopes-Cendes, Iscia;Steiner, Carlos E.;Silveira, Isabel;Pinto-Junior, Walter;Maciel, Jayme A.;Rouleau, Guy A.;
Arquivos de Neuro-Psiquiatria , 1996, DOI: 10.1590/S0004-282X1996000300009
Abstract: the spinocerebellar ataxias (scas) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. to date, seven different genes causing autosomal dominant sca have been mapped: sca1, sca2, machado-joseph disease (mjd)/sca3, sca4, sca5, sca7 and dentatorubropallidoluysian atrophy (drpla). expansions of an unstable trinucleotide cag repeat cause three of these disorders: sca1, mjd/sca3 and drpla. we studied one brazilian family segregating an autosomal dominant type of sca. a total of ten individuals were examined and tested for the presence of the sca1, mjd and drpla mutations. three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. the first complaint in all three patients was gait ataxia which progressed slowly over the years. six individuals showed one allele containing an expanded cag repeat in the sca1 gene. the mean size of the expanded allele was 48.2 cag units. instability of the expanded cag tract was seen in the two transmissions that were observed in this family. in both occasions there was a contraction of the cag tract. our study demonstrates that sca1 occurs in the brazilian population. in addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in scas.
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