Abstract
Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases which are caused by diverse genetic mutations in a variety of different genes. We have identified RGS8, a regulator of G-protein signaling, as one of the genes which are dysregulated in different mouse models of SCA (e.g., SCA1, SCA2, SCA7, and SCA14). In the moment, little is known about the role of RGS8 for pathogenesis of spinocerebellar ataxia. We have studied the expression of RGS8 in the cerebellum in more detail and show that it is specifically expressed in mouse cerebellar Purkinje cells. In a mouse model of SCA14 with increased PKCγ activity, RGS8 expression was also increased. RGS8 overexpression could partially counteract the negative effects of DHPG-induced mGluR1 signaling for the expansion of Purkinje cell dendrites. Our results suggest that the increased expression of RGS8 is an important mediator of mGluR1 pathway dysregulation in Purkinje cells. These findings provide new insights in the role of RGS8 and mGluR1 signaling in Purkinje cells and for the pathology of SCAs.
Highlights
Spinocerebellar ataxias (SCAs) are a heterogeneous group of progressive genetic disorders with degeneration and dysfunction of the cerebellum (Chen et al, 2005; Gatchel et al, 2008; Dansithong et al, 2015; Klockgether et al, 2019)
We studied the changes of RGS8 in the SCA14 mouse model in more detail and found that upregulation of RGS8 is associated with increased metabotropic glutamate receptor 1 (mGluR1) signaling
We have further compared these genes to transcriptional changes in a mouse model of SCA14 (Ji et al, 2014; Shimobayashi et al, 2016), and have identified three genes which were dysregulated in all three mouse models
Summary
Spinocerebellar ataxias (SCAs) are a heterogeneous group of progressive genetic disorders with degeneration and dysfunction of the cerebellum (Chen et al, 2005; Gatchel et al, 2008; Dansithong et al, 2015; Klockgether et al, 2019). Most SCA mutations cause cerebellar damage and dysfunction typically resulting from Purkinje cell degeneration (Chen et al, 2005; Klockgether et al, 2019). Due to the diversity of the affected genes, it is not clear in the moment whether there is a single disease mechanism causing the diverse forms. SCA1 and SCA7 mouse models have been chosen as the representatives of group I repeat expansion SCAs, and 27 molecules with transcriptional changes in both mouse models have been identified by using a microarray-based gene profiling strategy (Gatchel et al, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
