scholarly journals A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes

2021 ◽  
Author(s):  
Eva Haas ◽  
Rana D. Incebacak ◽  
Thomas Hentrich ◽  
Chrisovalantou Huridou ◽  
Thorsten Schmidt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Brain Regions ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
The Novel ◽  
Spinocerebellar Ataxia Type 3 ◽  
Transcriptional Changes ◽  
Cerebellar Tissue ◽  
Type 3 ◽  
Polyq Expansion

AbstractSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

scholarly journals A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes

2021 ◽  
Author(s):  
Eva Haas ◽  
Rana D. Incebacak ◽  
Thomas Hentrich ◽  
Chrisovalantou Huridou ◽  
Thorsten Schmidt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Brain Regions ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
The Novel ◽  
Spinocerebellar Ataxia Type 3 ◽  
Transcriptional Changes ◽  
Cerebellar Tissue ◽  
Type 3 ◽  
Polyq Expansion

Abstract Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of SCA3 the knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

scholarly journals A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

2020 ◽  
Author(s):  
Eva Haas ◽  
Rana D. Incebacak ◽  
Thomas Hentrich ◽  
Yacine Maringer ◽  
Thorsten Schmidt ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Brain Regions ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
The Novel ◽  
Aggregate Formation ◽  
Transcriptional Changes ◽  
Cerebellar Tissue ◽  
Polyq Expansion

AbstractBackgroundSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism.MethodsHere, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model.ResultsThe novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.ConclusionThe novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.

scholarly journals Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis

2021 ◽  
Author(s):  
Kristen H Schuster ◽  
Annie J Zalon ◽  
Hongjiu Zhang ◽  
Danielle M DiFranco ◽  
Nicholas R Stec ◽  
...  
Keyword(s):  
Protein A ◽  
Brain Regions ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Mutant Form ◽  
Disease Pathogenesis ◽  
Spinocerebellar Ataxia Type 3 ◽  
Reporter Mice ◽  
Transcriptional Changes ◽  
Type 3

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression network analysis revealed dysfunction in SCA3 oligodendrocyte maturation. These results reflect a toxic gain of function mechanism, as ATXN3 knockout mice do not exhibit any impairments in oligodendrocyte maturation. Genetic crosses to reporter mice revealed a marked reduction in mature oligodendrocytes in SCA3-disease vulnerable brain regions and ultrastructural microscopy confirmed abnormalities in axonal myelination. Further study of isolated oligodendrocyte precursor cells from SCA3 mice established that this impairment in oligodendrocyte maturation is a cell autonomous process. We conclude that SCA3 is not simply a disease of neurons and the search for therapeutic strategies and disease biomarkers will need to account for non-neuronal involvement in SCA3 pathogenesis.

scholarly journals Homozygous spinocerebellar ataxia type 3 in China: a case report

2021 ◽  
Vol 49 (6) ◽  
pp. 030006052110213
Author(s):  
Yuchao Chen ◽  
Dan Li ◽  
Minger Wei ◽  
Menglu Zhou ◽  
Linan Zhang ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Clinical Phenotype ◽  
Gene Dosage ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Contraction Pattern ◽  
Spinocerebellar Ataxia Type 3 ◽  
Type 3 ◽  
Stable Transmission

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene ( ATXN3). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of ATXN3 are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient’s family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

scholarly journals Dystonia in Patients with Spinocerebellar Ataxia 3 - Machado-Joseph disease: An Underestimated Diagnosis?

2018 ◽  
Vol 12 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Ligia Maria Perrucci Catai ◽  
Carlos Henrique Ferreira Camargo ◽  
Adriana Moro ◽  
Gustavo Ribas ◽  
Salmo Raskin ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Movement Disorders ◽  
Disease Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Generalized Dystonia ◽  
Machado Joseph Disease ◽  
Sca3 Patient ◽  
Type 3

Background:Spinocerebellar Ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is characterized by cerebellar, central and peripheral symptoms, including movement disorders. Dystonia can be classified as hereditary and neurodegenerative when present in SCA3.Objective:The objective of this study was to evaluate the dystonia characteristics in patients with MJD.Method:We identified all SCA3 patients with dystonia from the SCA3 HC-UFPR database, between December 2015 and December 2016.Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data. Standardized evaluation was carried out through the classification of Movement Disorders Society of 2013 and Burke Fahn-Marsden scale (BFM).Results:Amongst the presenting some common characteristics, 381 patients with SCA3, 14 (3.7%) subjects presented dystonia: 5 blepharospasm, 1 cervical dystonia, 3 oromandibular, 3 multifocal and 2 generalized dystonia. Regarding dystonia's subtypes, 71.4% had SCA3 subtype I and 28.6% SCA3 subtype II. The average age of the disease onset was 40±10.7 years; the SCA3 disease duration was 11.86± 6.13 years; the CAG repeat lengths ranged from 75 to 78, and the BFM scores ranged from 1.0 to 40. There was no correlation between the dystonia severity and CAG repeat lengths or the SCA3 clinical evolution.Conclusion:Dystonia in SCA3 is frequent and displays highly variable clinical profiles and severity grades. Dystonia is therefore a present symptom in SCA3, which may precede the SCA3 classic symptoms. Dystonia diagnosis is yet to be properly recognized within SCA3 patient.

scholarly journals A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript

2014 ◽  
Vol 24 (5) ◽  
pp. 1211-1224 ◽  
Author(s):  
Biswarathan Ramani ◽  
Ginny M. Harris ◽  
Rogerio Huang ◽  
Takahiro Seki ◽  
Geoffrey G. Murphy ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinocerebellar Ataxia ◽  
Disease Gene ◽  
Spinocerebellar Ataxia Type ◽  
Gene Transcript ◽  
Aberrant Splicing ◽  
Spinocerebellar Ataxia Type 3 ◽  
Type 3 ◽  
Knockin Mouse

scholarly journals Cerebellar neuronal dysfunction accompanies early motor symptoms in Spinocerebellar Ataxia Type 3 and is partially alleviated upon chronic citalopram treatment

2021 ◽  
Author(s):  
KJ Palarz ◽  
A Neves-Carvalho ◽  
S Duarte-Silva ◽  
P Maciel ◽  
K Khodakhah
Keyword(s):  
Mouse Model ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Spinocerebellar Ataxia ◽  
Cell Activity ◽  
Spinocerebellar Ataxia Type ◽  
Neuronal Dysfunction ◽  
Spinocerebellar Ataxia Type 3 ◽  
Cell Dysfunction ◽  
Type 3

ABSTRACTSpinocerebellar ataxia type 3 (SCA3) is an adult-onset, progressive ataxia with no current disease modifying treatments. SCA3 patients have mild degeneration of the cerebellum, a brain area involved in motor coordination and maintenance of balance, as well as of the brainstem, of the spinal cord and of other movement-related subcortical areas. However, both SCA3 patients and SCA3 mouse models present clinical symptoms before any gross pathology is detectable, which suggests neuronal dysfunction precedes neurodegeneration, and opens an opportunity for therapeutic intervention. Such observations also raise the question of what triggers these abnormal motor phenotypes. Purkinje cells are the major computational unit within the cerebellum and are responsible for facilitating coordinated movements. Abnormal Purkinje cell activity is sufficient to cause ataxia. In this study, we show that the CMVMJD135 mouse model of SCA3 has dysfunctional deep cerebellar nuclei and Purkinje cells. Both cell types have increased irregularity as measured by inter-spike interval coefficient of variation. Purkinje cell dysfunction is likely a combination of intrinsic and extrinsic (synaptic) dysfunction. Interestingly, Citalopram, a selective serotonin reuptake inhibitor previously shown to alleviate disease in CMVMJD135 mice, also improved cerebellar neuron function in the CMVMJD135 mouse model. Specifically, we found that Purkinje cell dysfunction when synaptic transmission is intact was alleviated with citalopram treatment, however, intrinsic Purkinje cell dysfunction was not alleviated. Altogether, our findings suggest that cerebellar neuronal dysfunction contributes to the onset of SCA3 motor dysfunction and that citalopram, while effective at alleviating the motor phenotype, does not restore Purkinje cell intrinsic activity in SCA3. A novel therapeutic approach that combines citalopram with another therapeutic that targets this intrinsic dysfunction in a complementary manner might further reduce disease burden in SCA3.

scholarly journals Silencing of genes responsible for polyQ diseases using chemically modified single-stranded siRNAs

2017 ◽  
Vol 63 (4) ◽  
Author(s):  
Agnieszka Fiszer ◽  
Marianna E Ellison-Klimontowicz ◽  
Wlodzimierz J Krzyzosiak
Keyword(s):  
Genetic Disorders ◽  
Mutant Gene ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Mutation Site ◽  
Protein Levels ◽  
Cellular Models ◽  
Polyq Diseases ◽  
Type 3

Polyglutamine (polyQ) diseases comprise a group of nine genetic disorders that are caused by the expansion of the CAG triplet repeat, which encodes glutamine, in unrelated single genes. The pathogenesis is caused by the disruption of cellular pathways by the expression products of the mutant gene, i.e., proteins containing polyQ tracts and mutant transcripts. In considering oligonucleotide (ON)-based therapeutic approaches for polyQ diseases, the very attractive CAG repeat-targeting strategy offers selective silencing of the mutant allele by directly targeting the mutation site. CAG repeat-targeting miRNA-like siRNAs have been shown to specifically inhibit mutant gene expression, and their characteristic feature is the formation of mismatches in their interactions with the target site. Here, we designed novel single-stranded siRNAs that contain base substitutions and chemical modifications and tested these oligonucleotides in cellular models of Huntington’s disease (HD), spinocerebellar ataxia type 3 (SCA3) and dentatorubral-pallidoluysian atrophy (DRPLA), including HD mouse striatal cells. Selected siRNAs caused the efficient and selective downregulation of the mutant protein levels.

scholarly journals Polyglutamine-expanded ataxin-3: a target engagement marker for Spinocerebellar ataxia type 3 in peripheral blood

2021 ◽  
Author(s):  
Jeannette Huebener-Schmid ◽  
Kirsten Kuhlbrodt ◽  
Julien Peladan ◽  
Jennifer Faber ◽  
Magda M Santana ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Clinical Parameters ◽  
Target Engagement ◽  
Spinocerebellar Ataxia Type 3 ◽  
Curative Therapy ◽  
Cag Repeat Expansion ◽  
Type 3

Abstract Spinocerebellar ataxia type 3 is a rare neurodegenerative disease, caused by a CAG repeat expansion leading to polyglutamine elongation in the ataxin-3 protein. While no curative therapy is yet available, preclinical gene silencing approaches to reduce polyglutamine-toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. We developed a novel ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid. Statistical analyses revealed a correlation with clinical parameters and a stability of polyglutamine-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phase.

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