scholarly journals Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signalled to DNA damage by Ataxia Telangiectasia Mutated kinase

2019 ◽  
Author(s):  
Celeste E. Suart ◽  
Alma M. Perez ◽  
Ismael Al-Ramahi ◽  
Tamara Maiuri ◽  
Juan Botas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spinocerebellar Ataxia ◽  
Ataxia Telangiectasia ◽  
Neurodegenerative Disorder ◽  
Age At Onset ◽  
Spinocerebellar Ataxia Type ◽  
Ataxia Telangiectasia Mutated ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Expansion

ABSTRACTSpinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington’s Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

scholarly journals Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

2014 ◽  
Vol 51 (7) ◽  
pp. 479-486 ◽  
Author(s):  
Sophie Tezenas du Montcel ◽  
Alexandra Durr ◽  
Maria Rakowicz ◽  
Lorenzo Nanetti ◽  
Perrine Charles ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Age At Onset ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1

scholarly journals Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Terri M Driessen ◽  
Paul J Lee ◽  
Janghoo Lim
Keyword(s):  
Mouse Models ◽  
Spinocerebellar Ataxia ◽  
Inferior Olive ◽  
Neurodegenerative Disorder ◽  
Biological Pathways ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Molecular Alterations ◽  
First Time

The neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) affects the cerebellum and inferior olive, though previous research has focused primarily on the cerebellum. As a result, it is unknown what molecular alterations are present in the inferior olive, and whether these changes are found in other affected tissues. This study addresses these questions for the first time using two different SCA1 mouse models. We found that differentially regulated genes in the inferior olive segregated into several biological pathways. Comparison of the inferior olive and cerebellum demonstrates that vulnerable tissues in SCA1 are not uniform in their gene expression changes, and express largely discrete but some commonly enriched biological pathways. Importantly, we also found that brain-region-specific differences occur early in disease initiation and progression, and they are shared across the two mouse models of SCA1. This suggests different mechanisms of degeneration at work in the inferior olive and cerebellum.

scholarly journals CRISPR/Cas9-based silencing of the ATXN1 gene in Spinocerebellar ataxia type 1 (SCA1) fibroblasts

2020 ◽  
Author(s):  
Francesca Salvatori ◽  
Mariangela Pappadà ◽  
Mariaconcetta Sicurella ◽  
Mattia Buratto ◽  
Valentina Simioni ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Rna Seq ◽  
Coding Region ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyq Tract

AbstractSpinocerebellar Ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a gain-of-function protein with toxic activities, containing an expanded polyQ tract in the coding region. Actually, there are no treatments available to delay the onset, stop or slow down the progression of this pathology. Many approaches developed over the years involve the use of siRNAs and antisense oligonucleotides (ASOs). Here we develop and validate a CRISPR/Cas9 therapeutic strategy in fibroblasts isolated from SCA1 patients. We started from the screening of 10 different sgRNAs able to recognize regions upstream and downstream the CAG repeats, in exon 8 of ATXN1 gene. The two most promising sgRNAs, G3 and G8, whose efficiency was evaluated with an in vitro system, significantly downregulated the ATXN 1 protein expression. This downregulation was due to the introduction of indels mutations into the ATXN1 gene. Notably, with an RNA-seq analysis, we demonstrated minimal off-target effects of our sgRNAs. These preliminary results support CRISPR/Cas9 as a promising approach for treated polyQ-expanded diseases.

scholarly journals Functional Annotation of Small Noncoding RNAs Target Genes Provides Evidence for a Deregulated Ubiquitin-Proteasome Pathway in Spinocerebellar Ataxia Type 1

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Stephan Persengiev ◽  
Ivanela Kondova ◽  
Ronald E. Bontrop
Keyword(s):  
Spinocerebellar Ataxia ◽  
Target Genes ◽  
Neurodegenerative Disorder ◽  
Noncoding Rnas ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Small Noncoding Rnas ◽  
Ubiquitin Proteasome

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by the expansion of CAG repeats in the ataxin 1 (ATXN1) gene. In affected cerebellar neurons of patients, mutant ATXN1 accumulates in ubiquitin-positive nuclear inclusions, indicating that protein misfolding is involved in SCA1 pathogenesis. In this study, we functionally annotated the target genes of the small noncoding RNAs (ncRNAs) that were selectively activated in the affected brain compartments. The primary targets of these RNAs, which exhibited a significant enrichment in the cerebellum and cortex of SCA1 patients, were members of the ubiquitin-proteasome system. Thus, we identified and functionally annotated a plausible regulatory pathway that may serve as a potential target to modulate the outcome of neurodegenerative diseases.

scholarly journals Enhanced Phosphorylation of Transcription Factor Sp1 in Response to Herpes Simplex Virus Type 1 Infection Is Dependent on the Ataxia Telangiectasia-Mutated Protein

2007 ◽  
Vol 81 (18) ◽  
pp. 9653-9664 ◽  
Author(s):  
Satoko Iwahori ◽  
Noriko Shirata ◽  
Yasushi Kawaguchi ◽  
Sandra K. Weller ◽  
Yoshitaka Sato ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. In ATM-deficient cells or cells silenced for ATM expression by short hairpin RNA targeting, hyperphosphorylation of Sp1 was prevented even as HSV-1 infection progressed. Mutational analysis of putative ATM phosphorylation sites on Sp1 and immunoblot analysis with phosphopeptide-specific Sp1 antibodies clarified that at least Ser-56 and Ser-101 residues on Sp1 became phosphorylated upon HSV-1 infection. Serine-to-alanine mutations at both sites on Sp1 considerably abolished hyperphosphorylation of Sp1 upon infection. Although ATM phosphorylated Ser-101 but not Ser-56 on Sp1 in vitro, phosphorylation of Sp1 at both sites was not detected at all upon infection in ATM-deficient cells, suggesting that cellular kinase(s) activated by ATM could be involved in phosphorylation at Ser-56. Upon viral infection, Sp1-dependent transcription in ATM expression-silenced cells was almost the same as that in ATM-intact cells, suggesting that ATM-dependent phosphorylation of Sp1 might hardly affect its transcriptional activity during the HSV-1 infection. ATM-dependent Sp1 phosphorylation appears to be a global response to various DNA damage stress including viral DNA replication.

Striatal dopamine nerve terminal markers but not nigral cellularity are reduced in spinocerebellar ataxia type 1

Neurology ◽  
1997 ◽  
Vol 48 (4) ◽  
pp. 1109-1111 ◽  
Author(s):  
S. J. Kish ◽  
M. Guttman ◽  
Y. Robitaille ◽  
M. El-Awar ◽  
L. -J. Chang ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Nerve Terminal ◽  
Striatal Dopamine ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1
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