scholarly journals Genetic Modeling of the Neurodegenerative Disease Spinocerebellar Ataxia Type 1 in Zebrafish

2021 ◽  
Vol 22 (14) ◽  
pp. 7351
Author(s):  
Mohamed A. Elsaey ◽  
Kazuhiko Namikawa ◽  
Reinhard W. Köster
Keyword(s):  
Spinocerebellar Ataxia ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxias ◽  
Spinocerebellar Ataxia Type 1 ◽  
Reporter Protein ◽  
Fluorescent Reporter ◽  
Larval Stages

Dominant spinocerebellar ataxias (SCAs) are progredient neurodegenerative diseases commonly affecting the survival of Purkinje cells (PCs) in the human cerebellum. Spinocerebellar ataxia type 1 (SCA1) is caused by the mutated ataxin1 (Atx1) gene product, in which a polyglutamine stretch encoded by CAG repeats is extended in affected SCA1 patients. As a monogenetic disease with the Atx1-polyQ protein exerting a gain of function, SCA1 can be genetically modelled in animals by cell type-specific overexpression. We have established a transgenic PC-specific SCA1 model in zebrafish coexpressing the fluorescent reporter protein mScarlet together with either human wild type Atx1[30Q] as control or SCA1 patient-derived Atx1[82Q]. SCA1 zebrafish display an age-dependent PC degeneration starting at larval stages around six weeks postfertilization, which continuously progresses during further juvenile and young adult stages. Interestingly, PC degeneration is observed more severely in rostral than in caudal regions of the PC population. Although such a neuropathology resulted in no gross locomotor control deficits, SCA1-fish with advanced PC loss display a reduced exploratory behaviour. In vivo imaging in this SCA1 model may help to better understand such patterned PC death known from PC neurodegeneration diseases, to elucidate disease mechanisms and to provide access to neuroprotective compound characterization in vivo.

Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes

1995 ◽  
Vol 4 (9) ◽  
pp. 1585-1590 ◽  
Author(s):  
David C. Rubinsztein ◽  
Jayne Leggo ◽  
Gerhard A. Coetzee ◽  
Ryan A. Irvine ◽  
Michael Buckley ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Spinocerebellar Ataxia ◽  
Sequence Variation ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Machado Joseph Disease

Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene

1997 ◽  
Vol 74 (5) ◽  
pp. 488-493 ◽  
Author(s):  
Pornprot Limprasert ◽  
Nassim Nouri ◽  
Chamnong Nopparatana ◽  
Prescott L. Deininger ◽  
Bronya J.B. Keats
Keyword(s):  
Spinocerebellar Ataxia ◽  
Comparative Studies ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1

scholarly journals Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset

2021 ◽  
Author(s):  
Carlo Wilke ◽  
David Mengel ◽  
Ludger Schoels ◽  
Holger Hengel ◽  
Maria Rakowicz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxias ◽  
Volumetric Mri ◽  
Spinocerebellar Ataxia Type 1 ◽  
Neurofilament Light ◽  
Clinical Onset

Background and Objectives. Neurofilament light (NfL) appears a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of spinocerebellar ataxia type 1 (SCA1). We here hypothesised that NfL is increased not only at the ataxic stage of SCA1, but also at its - likely most treatment-relevant - preataxic stage. Methods. We assessed serum (sNfL) and cerebrospinal fluid (cNfL) levels of NfL in both preataxic and ataxic SCA1, leveraging a multicentric cohort of 40 SCA1 carriers (23 preataxic, 17 ataxic) and >80 controls, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage (11 carriers). Results. sNfL levels were increased with high age-corrected effect sizes at the preataxic (r=0.62) and ataxic stage (r=0.63), paralleling increases of cNfL levels. In preataxic subjects, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic subjects with actually observed ataxia onset. sNfL increases were detected already in preataxic SCA1 subjects without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials using the reduction of sNfL as endpoint. Conclusions. sNfL levels might thus provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic subjects regarding proximity-to-onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.

scholarly journals Ataxin-1 oligomers induce local spread of pathology and decreasing them by passive immunization slows Spinocerebellar ataxia type 1 phenotypes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Cristian A Lasagna-Reeves ◽  
Maxime WC Rousseaux ◽  
Marcos J Guerrero-Munoz ◽  
Luis Vilanova-Velez ◽  
Jeehye Park ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Motor Coordination ◽  
Passive Immunization ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Passive Immunotherapy ◽  
Disease Phenotypes ◽  
Local Spread

Previously, we reported that ATXN1 oligomers are the primary drivers of toxicity in Spinocerebellar ataxia type 1 (SCA1; Lasagna-Reeves et al., 2015). Here we report that polyQ ATXN1 oligomers can propagate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculation. Our data also show that targeting these oligomers with passive immunotherapy leads to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span. These findings provide evidence that oligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular oligomers can mildly modify disease phenotypes.

scholarly journals Mood alterations in mouse models of Spinocerebellar Ataxia type 1

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.

scholarly journals Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia)

2019 ◽  
Vol 2 (2) ◽  
pp. 62-73
Author(s):  
Lev Goldfarb ◽  
Fedor Platonov
Keyword(s):  
Spinocerebellar Ataxia ◽  
Age Of Onset ◽  
Selection Index ◽  
Genetic Identification ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Public Health Burden ◽  
The Republic

Over the past several decades, more than 500 cases of Autosomal dominant spinocerebellar ataxia type 1 (SCA1) have been identified in the Republic of Sakha (Yakutia) of North-Eastern Siberia. The disease leads to long-term disability and death, making it a serious public health burden. The prevalence of SCA1 in the indigenous Sakha population has been steadily increasing since the 1970s. It has recently stabilized at a level of 45-53 per 100,000 due to efforts undertaken to limit its further spread. We describe results of a multi-year study of SCA1 in the Sakha population, including molecular genetics, distribution, clinical, electrophysiological and histopathological characteristics. Each studied patient had a mutation in the coding region of the ATXN1 gene on chromosome 6p22.3. The mutation presents as an uncontrolled increase in the number of trinucleotide CAG repeats from normal 25-32 to 39-72 with a loss of a CAT bridge in the middle of the CAG stretch. The number of continuous CAG triplets in the mutant ATXN1 gene correlates with the age of onset and the severity of the disease. The instability of this genomic segment is manifested in meiosis: the number of CAG repeats in a mutant gene increases in transmission from the father by an average of +3.04 repetitions and from the mother by +0.182 repetitions. The total number of repeats transmitted from one generation to another in the Sakha population is on average +1.614, which explains the increase in SCA1 prevalence. Patients from three spatially separate geographic regions of the Republic have the same haplotype, which confirms the origin of the mutation from a common ancestor about 37 generations ago. SCA1 patients in Mongolia, China and the U.S. show a different haplotype. To determine the potential of SCA1 for further spread, the fertility rates of the ATXN1 mutation carriers were evaluated and the Crow selection index calculated. The resulting score of 0.19 indicates that the mutation has little chance of being eliminated from the population without targeted preventive measures.

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.

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