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Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum

ABSTRACT: The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well known. Here, we characterized pathology in the motor cortex of a SCA1 mouse model and performed RNA sequencing in this brain region to investigate the impact of mutant ataxin-1 towards transcriptomic alterations. We identified progressive cortical pathology and significant transcriptomic changes in the motor cortex of a SCA1 mouse model. We also identified progressive, region-specific, colocalization of p62 with mutant ataxin-1 aggregates in broad brain regions, but not the cerebellum or brainstem. A cross-regional comparison of the SCA1 cortical and cerebellar transcriptomic changes identified both common and unique gene expression changes between the two regions, including shared synaptic dysfunction and region-specific kinase regulation. These findings suggest that the cortex is progressively impacted via both shared and region-specific mechanisms in SCA1.

ORGANISM(S): Mus musculus

PROVIDER: GSE211678 | GEO | 2022/08/22

REPOSITORIES: GEO

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Project description:Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation, and affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript, soluble and insoluble protein levels were increased. In more vulnerable cerebellum the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated selective induction of Fbxw8 in old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissue-specific effects, which may be partially alleviated by the induction of FBXW8. Factorial design comparing Atxn2 knock-in mice with wild type littermates in three different tissues (brainstem, cerebellum, liver)

Project description:A number of human neurodegenerative diseases result from the expansion of a glutamine repeat within the disease-causing protein. Spinocerebellar ataxia type1 is one such disease, caused by expansion of a polyglutamine tract in the novel protein ataxin-1. To faithfully model SCA1 in the mouse, we generated knock-in mice carrying 154 CAG repeats in the mouse Sca1 locus. These mice reproduced many aspects of the human disease. Despite ubiquitous expression of the mutant protein, they developed slowly progressive selective neurodegeneration , which is most distinct in Purkinje cells and spinal cord. Alterations in gene expression have been proposed to be involved in the pathogenesis of polyglutamine disease including SCA1, but the changes of gene expression in an authentic disease model have not been characterized. We believe that knowledge of these genes will give insight into the pathophysiology of SCA1 and may ultimately be relevant to the treatment of SCA1.,We will determine gene expression patterns in the cerebellum and forebrain at three different time points.,We propose that the genes whose expression is affected by mutant ataxin-1 expression are effectors for neuronal dysfunction and neuronal degeneration in the knock-in mice. We also hypothesize the difference in the expression levels of these genes accounts for selective vulnerability of neurons.,We will examine three time points: 4 weeks, 11 weeks, and 20 weeks of age. We have shown that the mice developed motor incoordination as revealed by rotating rod test as early as 5 weeks of age but it was not until 10 weeks that they start showing clear neurological phenotype such as clasping. At each point, we will compare the pattern between the mutant and wild-type littermate. Animals will be prepared and sacrificed by a standard procedure. Cerebellum and spinal cord are the most affected areas whereas forebrain shows less neurodegeneration. Tissue will be rapidly dissected from cerebellum and forebrain, frozen in liquid nitrogen, and stored at ?80 C until analysis. Tissues will be sent to the centers (as opposed to RNA). We will be providing 9 tissue samples from three litters for each time point to mitigate any expression differences resulting from subtle differences of procedure or environment where the mice grow.

Project description:A number of human neurodegenerative diseases result from the expansion of a glutamine repeat within the disease-causing protein. Spinocerebellar ataxia type1 is one such disease, caused by expansion of a polyglutamine tract in the novel protein ataxin-1. To faithfully model SCA1 in the mouse, we generated knock-in mice carrying 154 CAG repeats in the mouse Sca1 locus. These mice reproduced many aspects of the human disease. Despite ubiquitous expression of the mutant protein, they developed slowly progressive selective neurodegeneration , which is most distinct in Purkinje cells and spinal cord. Alterations in gene expression have been proposed to be involved in the pathogenesis of polyglutamine disease including SCA1, but the changes of gene expression in an authentic disease model have not been characterized. We believe that knowledge of these genes will give insight into the pathophysiology of SCA1 and may ultimately be relevant to the treatment of SCA1. We will determine gene expression patterns in the cerebellum and forebrain at three different time points. We propose that the genes whose expression is affected by mutant ataxin-1 expression are effectors for neuronal dysfunction and neuronal degeneration in the knock-in mice. We also hypothesize the difference in the expression levels of these genes accounts for selective vulnerability of neurons. We will examine three time points: 4 weeks, 11 weeks, and 20 weeks of age. We have shown that the mice developed motor incoordination as revealed by rotating rod test as early as 5 weeks of age but it was not until 10 weeks that they start showing clear neurological phenotype such as clasping. At each point, we will compare the pattern between the mutant and wild-type littermate. Animals will be prepared and sacrificed by a standard procedure. Cerebellum and spinal cord are the most affected areas whereas forebrain shows less neurodegeneration. Tissue will be rapidly dissected from cerebellum and forebrain, frozen in liquid nitrogen, and stored at ?80 C until analysis. Tissues will be sent to the centers (as opposed to RNA). We will be providing 9 tissue samples from three litters for each time point to mitigate any expression differences resulting from subtle differences of procedure or environment where the mice grow. Keywords: time-course

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Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum

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