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Cerebellar Purkinje cells in Ki91 mice show neurodegeneration. (B-D) The Purkinje cells cell bodies and dendrites from Ki91 animals showed much weaker Calbindin D-28 k-IR compared to (A) the Purkinje cells from WT animals. The Ki91 Purkinje cell bodies were smaller and irregular. (B, D) Purkinje cells with more than one dendrite (white arrows) were readily visible in Ki91 animals. DAPI nuclear staining was omitted for clarity. (E-G) Quantification of Calbindin D-28 k immunoreactive Purkinje cells in Ki91 and WT mice. (E) Loss of Purkinje cells in both nodular zone (lobule 10) and the anterior region (lobule 4/5) of the Ki91 cerebellum was mild. (F) Weakly immunoreactive subpopulation of Purkinje cells with invisible primary dendrites and (G) a subpopulation with an unstained nuclear compartment were significantly overrepresented in Ki91 cerebella compared to WT animals (Student's t-test, ***p b 0.01, **p b 0.01 and *p b 0.05).
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Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei...
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... magnifi- cation also revealed a much weaker immunofluorescent Calbindin D- 28 k signal, resulting in the presence of an abundant population of Purkinje cells where primary dendrite was invisible in knock-in sections (Figs. 8B, C and D). Moreover, the Purkinje cell bodies in the knock-in mice were smaller and irregular compared to those in WT mice (Fig. 8A). Examination of single confocal planes from these image stacks also revealed that there was a relatively abundant population of Purkinje cells where the cell nuclei did not contain the Calbindin D- 28 k signal. In addition, Purkinje cells with more than one dendrite were readily found in knock-in sections (Figs. 8B and D), but they ...
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Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, th...
Citations
... Neuropathological findings in SCA3 mice are ameliorated by TUDCA. Widespread histological changes in the CNS have been described in several mouse models of SCA3 (29,49,50). Treatment with TUDCA prevented loss of cholinergic motor neurons in the cervical and thoracic spinal cord of CMVMJD135 mice ( Figure 2, A and B) and normalized the number of pyknotic cells in pontine ( Figure 2C) and DCN ( Figure 2D). ...
Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the FXR. TUDCA was predicted to bind to the GR, similarly to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction, being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset, in pre-symptomatic subjects, and of FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3, and propose this readily available drug for clinical trials in SCA3 patients.
... This genetic alteration leads to slow neuronal degeneration in specific brain regions and the spinal cord, resulting in a wide variety of clinical manifestations, mainly motor-related [5][6][7]. Despite the welldescribed presence of neuronal death, other non-neuronal cells are involved in SCA3 pathogenesis [5,[8][9][10][11][12]. Astrogliosis is a common pathological feature in SCA3 that has also been found both in humans [5,10,11,13] and in animal models [14] of the disease, suggesting an important role of astrocytes in disease pathogenesis. ...
... Next, we performed a battery of well-established motor behavioral tests to obtain a full characterization of the double mutant to determine the effect of IP 3 R2 ablation in the disease presentation. In this longitudinal behavioral characterization, the animals were tested on several behavioral paradigms at 6,8,12,16,20,24, and 30 weeks of age (Figure 2a), corresponding to early, medium, and advanced disease stages, as previously described for Q135 mice [14]. The analysis of CAG length variation revealed that the Q135 and IP 3 R2 KO; Q135 mice carried a similar number of CAG repeats (Figure 2b), excluding an influence of CAG length variation on the behavior of the different test groups. ...
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.
... Although SCA3 and other polyglutamine expansion diseases have historically been studied through a neuron-centric focus, evidence of glial contributions to these diseases is gaining prominence in the literature. A role for gliosis has been demonstrated by increased glial fibrillary acidic protein (GFAP) staining in vulnerable brain regions in SCA3 mice 17,44,45 and higher serum GFAP levels in patients with SCA3. 32 Here, we show mice exhibit significant increases in Gln levels in the cerebellum and brainstem across all MRS-assessed time points. ...
Objective:
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated if repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).
Methods:
Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4 T MRS of cerebellum and brainstem was performed. Acquired MR group means were analyzed by two-way ANOVA mixed-effects sex-adjusted analysis with post-hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.
Results:
MR spectra yielded 15-16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease.
Interpretation:
SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as non-invasive treatment biomarkers in future SCA3 gene silencing trials. This article is protected by copyright. All rights reserved.
... Expansion of the CAG repeats number in ATXN3, which occurs between generations (intergenerational expansion), usually correlates with the accelerated disease progression in SCA3 patients (Maciel et al., 1995;Leotti et al., 2021). Also, our Ki91 mouse showed intergenerational expansion (Switonski et al., 2015), resulting in a spontaneous increase in the number of CAG repeats in our mouse colonies, yielding mice containing between 110 and 130 CAG repeats. Therefore, our goal was to boost the phenotype further, to enhance the mouse model suitability for preclinical therapy testing. ...
... We have previously shown inclusions in the SCA3 Ki91 mouse occurring in all brain regions (Switonski et al., 2015;Wiatr et al., 2019Wiatr et al., , 2021. In the Ki150 mouse model, we observed the formation of larger inclusions in all brain regions and also in higher numbers than observed in Ki91 and at a younger Ki150 age. ...
... Moreover the mouse models offered in the polyQ research are always compromised in their features such as lack of robust combination of preclinical, motor, molecular and neuropathological properties. For instance, the mild or moderate motor and molecular phenotype, accuracy of genetic constructs, full length human allele, and the concomitant presence of mouse allele are always compromised (Cemal et al., 2002;Switonski et al., 2015;Haas et al., 2022). The ideal model would have a quick phenotype for preclinical tests, have an entire human protein, uninterrupted CAG tract in mRNA and expansion phenotype. ...
Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease caused by CAG expansion in mutant ATXN3 gene. The resulting PolyQ tract in mutant ataxin-3 protein is toxic to neurons and currently no effective treatment exists. Function of both normal and mutant ataxin-3 is pleiotropic by their interactions and the influence on protein level. Our new preclinical Ki150 model with over 150 CAG/Q in ataxin-3 has robust aggregates indicating the presence of a process that enhances the interaction between proteins. Interactions in large complexes may resemble the real-life inclusion interactions and was never examined before for mutant and normal ataxin-3 and in homozygous mouse model with long polyQ tract. We fractionated ataxin-3-positive large complexes and independently we pulled-down ataxin-3 from brain lysates, and both were followed by proteomics. Among others, mutant ataxin-3 abnormally interacted with subunits of large complexes such as Cct5 and 6, Tcp1, and Camk2a and Camk2b. Surprisingly, the complexes exhibit circular molecular structure which may be linked to the process of aggregates formation where annular aggregates are intermediate stage to fibrils which may indicate novel ataxin-3 mode of interactions. The protein complexes were involved in transport of mitochondria in axons which was confirmed by altered motility of mitochondria along SCA3 Ki150 neurites.
... Gene knockout or mutant disease models have been generated using numerous techniques, including chemical mutagenesis, such as with N-ethyl-N-nitrosourea (ENU) (de Angelis et al., 2000;Fossett et al., 1990;Hitotsumachi et al., 1985;Solnica-Krezel et al., 1994), engineered endonucleases such as transcription activator-like effector nucleases (TALENs) (Ke et al., 2016;Li et al., 2011), targeted genetic modification of mammalian embryonic stem cells to generate chimeric modified mice (Mak, 2007) or rescue of knockout models with humanised sequences containing diseaseassociated mutations (Switonski et al., 2015). However, these techniques can be laborious, chemical mutagenesis cannot be targeted to a specific region of the genome, and rescue with humanised mutation-bearing constructs is not always faithful to the expression level of the endogenous gene. ...
Over the past decade, CRISPR/Cas-based gene editing has become a powerful tool for generating mutations in a variety of model organisms, from Escherichia coli to zebrafish, rodents and large mammals. CRISPR/Cas-based gene editing effectively generates insertions or deletions (indels), which allow for rapid gene disruption. However, a large proportion of human genetic diseases are caused by single-base-pair substitutions, which result in more subtle alterations to protein function, and which require more complex and precise editing to recreate in model systems. Precise genome editing (PGE) methods, however, typically have efficiencies of less than a tenth of those that generate less-specific indels, and so there has been a great deal of effort to improve PGE efficiency. Such optimisations include optimal guide RNA and mutation-bearing donor DNA template design, modulation of DNA repair pathways that underpin how edits result from Cas-induced cuts, and the development of Cas9 fusion proteins that introduce edits via alternative mechanisms. In this Review, we provide an overview of the recent progress in optimising PGE methods and their potential for generating models of human genetic disease.
... Knock-in mice express mutant SCA gene under the control of the endogenous promoter. Previously, knock-in mouse models of SCA1 [36,37], SCA3 [38,39], and SCA7 [40] have been produced. Generally, endogenous promoters show weaker promoter activity, compared with exogenous promoters used in Tg mice. ...
... The SCA1 knock-in mice showed neuronal degeneration throughout the central nervous system, including cerebellar Purkinje cells, brainstem, and spinal motor neurons [41,42], resulting in progressive ataxia and premature death at around 50 weeks of age [36]. SCA3 knock-in mice that expressed ATXN3 carrying (relatively long) 91 CAG repeats showed slow progression of disease phenotype and only faint behavioral abnormality even at 1.5 years of age [39]. Similarly, another SCA3 knock-in mice that expressed ATXN3 comprising shorter 82 CAG repeats failed to exhibit motor defects even at 1 year of age, though intranuclear inclusions in various brain regions including Purkinje cells were present [38]. ...
Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient’s functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.
... A polyglutamine-expanded Atxn3 knockin mouse displays adult-onset motor decline; however, a larger expansion of the polyglutamine tract reflective of SCA type 1 is likely required to better model earlier onset (66). Nonetheless, this model reveals accumulation and aggregation of ATXN3 in adult brain cells, neuropathology in both neurons and glia, cerebellar degeneration with loss of Purkinje cells, and evidence of neuroinflammation (67). Collectively, these data highlight that compromised function of DUBs caused by LoF or hypomorphic mutations can cause NDDs, and current mouse models of these disorders are providing valuable insight into the molecular, cell, and physiological mechanisms of pathology. ...
Protein ubiquitination is a widespread multi-functional post-translational protein modification best known for its ability to direct protein degradation via the Ubiquitin Proteasome System (UPS). Ubiquitination is also reversible, and the human genome encodes over 90 deubiquitinating enzymes (DUBs), many of which appear to target specific subsets of ubiquitinated proteins. This review focuses on the roles of DUBs in neurodevelopmental disorders (NDDs). We present the current genetic evidence connecting 12 DUBs to a range of NDDs, and the functional studies implicating at least 19 additional DUBs as candidate NDD genes. We highlight how the study of DUBs in NDDs offers critical insights into the role of protein degradation during brain development. As one of the major known functions of a DUB is to antagonise the UPS, loss of function of DUB genes has been shown to culminate in loss of abundance of its protein substrates. The identification and study NDD DUB substrates in the developing brain is revealing that they regulate networks of proteins which themselves are encoded by NDD genes. We describe the new technologies which are enabling the full resolution of DUB protein networks in the developing brain with the view that this knowledge can direct the development of new therapeutic paradigms. That the abundance of many NDD proteins is regulated by the UPS presents an exciting opportunity to combat NDDs caused by haploinsufficiency, as the loss of abundance of NDD proteins can be potentially rectified by antagonising their UPS based degradation.
... In addition to biomarkers, the development and preclinical testing of potential therapeutics also requires animal models. Several mouse models of SCA3 have been developed over the years, using both transgenic and knock-in approaches, and many of these models recapitulate the ataxia-like behavior, inclusion pathology, and cerebellar degeneration expected of SCA3 (Ikeda et al., 1996;Cemal et al., 2002;Goti et al., 2004;Bichelmeier et al., 2007;Chou et al., 2008;Torashima et al., 2008;Boy et al., 2009;Boy et al., 2010;Silva-Fernandes et al., 2010;Simoes et al., 2012;Nobrega et al., 2013a;Silva-Fernandes et al., 2014;Ramani et al., 2015;Switonski et al., 2015;Haas et al., 2021). But the utility of mouse models doesn't stop there: researchers use mice to evaluate potential genetic modifiers and test mechanistic hypotheses. ...
... These inclusions resemble those seen in SCA3 patients ( Figures 3E,F), in that they were positive for ubiquitin (Supplementary Figures S6A,B, E,F) and could be detected using the common polyQ antibody clone 1C2 (Supplementary Figures S6C,D, G,H). This result is also consistent with phenotypes seen in other SCA3 mouse models (Ramani et al., 2015;Switonski et al., 2015;Haas et al., 2021), and with rare reports of inclusions in the cortex and Purkinje cells of SCA3 patients (Wilke et al., 2020). We also used our previously published immunoassay to measure the levels of polyQ-ATXN3 in the forebrain (Prudencio et al., 2020;Koike et al., 2021); this assay uses a capture antibody that is believed to target the pathogenic polyQ expansion (Miller et al., 2011). ...
... It is worth noting, however, that Purkinje cell loss, while occasionally observed (Scherzed et al., 2012), is not as prominent in SCA3 as it is in other spinocerebellar ataxias (Sachdev et al., 1982;Yuasa et al., 1986;Takiyama et al., 1994;Durr et al., 1996). It is unclear why this is the case, or why our mouse model, like other SCA3 mouse models (Cemal et al., 2002;Bichelmeier et al., 2007;Boy et al., 2010;Switonski et al., 2015;Haas et al., 2021), still shows some vulnerability in these cells. Indeed, the reasons underlying patterns of selective vulnerability in most neurodegenerative diseases are not understood, but an enticing hypothesis in the field of polyQ disease research is that the endogenous functions of the host protein influence its effects on different cell types. ...
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited cerebellar ataxia caused by the expansion of a polyglutamine (polyQ) repeat in the gene encoding ATXN3. The polyQ expansion induces protein inclusion formation in the neurons of patients and results in neuronal degeneration in the cerebellum and other brain regions. We used adeno-associated virus (AAV) technology to develop a new mouse model of SCA3 that recapitulates several features of the human disease, including locomotor defects, cerebellar-specific neuronal loss, polyQ-expanded ATXN3 inclusions, and TDP-43 pathology. We also found that neurofilament light is elevated in the cerebrospinal fluid (CSF) of the SCA3 animals, and the expanded polyQ-ATXN3 protein can be detected in the plasma. Interestingly, the levels of polyQ-ATXN3 in plasma correlated with measures of cerebellar degeneration and locomotor deficits in 6-month-old SCA3 mice, supporting the hypothesis that this factor could act as a biomarker for SCA3.
... Additionally, the models explore genetic pathways and mechanisms underlying disease development such as expansions, aberrant splicing, repeat-associated non-AUG (RAN) translation and RNA frameshifting. By using methods such as lentiviral transduction, microinjection with mRNA and transposase-mediated recombination, transgenic models were generated in yeast [87,88], human embryonic kidney (HEK) 293T cells [89][90][91], C. elegans [92][93][94][95], D. melanogaster [96][97][98], zebrafish [99][100][101][102], the mouse [27,[103][104][105][106][107][108][109][110][111][112][113], rat [83,114], sheep [115], pig [116,117] and monkey [118][119][120][121]. Additionally, patient-derived cells were reprogrammed into iPSCs and used to model polyQ diseases [122][123][124][125][126][127][128]. Nowadays, with the development of new genome-editing tools, CRISPR-Cas9 technology is most often used for modeling. ...
Polyglutamine (polyQ) diseases, including Huntington’s disease, are a group of late-onset progressive neurological disorders caused by CAG repeat expansions. Although recently, many studies have investigated the pathological features and development of polyQ diseases, many questions remain unanswered. The advancement of new gene-editing technologies, especially the CRISPR-Cas9 technique, has undeniable value for the generation of relevant polyQ models, which substantially support the research process. Here, we review how these tools have been used to correct disease-causing mutations or create isogenic cell lines with different numbers of CAG repeats. We characterize various cellular models such as HEK 293 cells, patient-derived fibroblasts, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and animal models generated with the use of genome-editing technology.
... These models hold the advantage of expressing a CAG expansion in the murine Atxn3 locus under endogenous regulatory elements and at physiological levels. Ramani and colleagues presented a KI line containing 82 CAG repeats in the murine Atxn3 locus [20,21], while Switonski and colleagues generated a mouse in which the murine Atxn3 gene was replaced by a humanized version with 91 CAG repeats [22]. Although these mice displayed aggregate formation and a mild phenotype, they did not reflect the complete human SCA3 phenotype. ...
... In this process we generated two different SCA3 KI founder lines, the 304Q, which was further bred heterozygous and homozygous and is the focus in this study. We also generated the 97Q line, whose properties are shown in comparison with the 304Q lines, since it is comparable to the lines of Ramani et al. [20] and Switonski et al. [22]. ...
... Due to the repetitive sequence in the donor vector, we obtained two founder lines one containing 97 CAA CAG repeats and one containing 304 CAA CAG interrupted repeats, leading to the corresponding length of polyQ-expansion in the Atxn3 protein (in the following called WT/97Q and WT/304Q mice) (Fig. 1A). WT/97Q mice serve merely as a control group, since they demonstrated comparable features as shown for the SCA3 KI mouse lines mice from Ramani [20] and Switonski [22]. To analyze a potential gene dosage effect, homozygous mice (304Q/304Q) were bred as well. ...
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 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 under- standing 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 sam- ples 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.
