Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP 3 R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3.

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 (IP 3 R2) is the predominant IP 3 R in mediating astrocyte somatic calcium signals, and genetically ablation of IP 3 R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP 3 R2 in the onset and progression of SCA3. For this, we tested whether IP 3 R2 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 IP 3 R2 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 IP 3 R2 deletion in astrocytes does not modify SCA3 progression.