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

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.

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Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1

Neuroscience ◽

10.1016/j.neuroscience.2015.01.003 ◽

2015 ◽

Vol 289 ◽

pp. 289-299 ◽

Cited By ~ 42

Author(s):

M. Cvetanovic ◽

M. Ingram ◽

H. Orr ◽

P. Opal

Keyword(s):

Mouse Models ◽

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Early Activation

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White matter atrophy in spinocerebellar ataxia type 1 mouse models revealed by serial optical coherence scanner (Conference Presentation)

Neural Imaging and Sensing 2018 ◽

10.1117/12.2289339 ◽

2018 ◽

Author(s):

Chao J. Liu ◽

Harry T. Orr ◽

Taner Akkin

Keyword(s):

White Matter ◽

Mouse Models ◽

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Optical Coherence ◽

Spinocerebellar Ataxia Type 1

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

10.1101/701953 ◽

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.

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Spinocerebellar Ataxia Type 1—Modeling the Pathogenesis of a Polyglutamine Neurodegenerative Disorder in Transgenic Mice

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/59.4.265 ◽

2000 ◽

Vol 59 (4) ◽

pp. 265-270 ◽

Cited By ~ 22

Author(s):

H. Brent Clark ◽

Harry T. Orr

Keyword(s):

Transgenic Mice ◽

Spinocerebellar Ataxia ◽

Neurodegenerative Disorder ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1

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Mood alterations in mouse models of Spinocerebellar Ataxia type 1

Scientific Reports ◽

10.1038/s41598-020-80664-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Melissa Asher ◽

Juao-Guilherme Rosa ◽

Marija Cvetanovic

Keyword(s):

Cognitive Decline ◽

Mouse Models ◽

Spinocerebellar Ataxia ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Motor Deficits ◽

Brain Pathology ◽

Spinocerebellar Ataxia Type 1 ◽

Plus Maze

AbstractSpinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.

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

10.1101/2020.07.04.187559 ◽

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.

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

Journal of Nucleic Acids ◽

10.1155/2012/672536 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 4

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.

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