Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.
ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga/4805-017 Guimarães, Portugal.
Int J Mol Sci. 2023 Jun 25;24(13):10606. doi: 10.3390/ijms241310606.
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 (IPR2) is the predominant IPR in mediating astrocyte somatic calcium signals, and genetically ablation of IPR2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IPR2 in the onset and progression of SCA3. For this, we tested whether IPR2 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 IPR2 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 IPR2 deletion in astrocytes does not modify SCA3 progression.
脊髓小脑共济失调 3 型（SCA3）是一种罕见的神经退行性疾病，由ataxin-3 蛋白（ATXN3）内异常的多聚谷氨酰胺扩展引起。这导致特定脑和脊髓区域的神经变性，导致运动功能逐渐丧失。尽管神经元死亡，但包括星形胶质细胞在内的非神经元细胞也参与了 SCA3 的发病机制。星形胶质细胞增生是 SCA3 患者和疾病动物模型的常见病理特征。然而，星形胶质细胞对 SCA3 的贡献尚不清楚。三磷酸肌醇受体 2（IPR2）是介导星形胶质体细胞钙信号的主要 IPR，IPR2 的基因缺失已广泛用于研究星形胶质细胞功能。在这里，我们旨在研究 IPR2 在 SCA3 发病和进展中的相关性。为此，我们测试了 IPR2 耗竭和随后抑制全局星形胶质细胞钙信号是否会导致 SCA3 小鼠模型，即 CMVMJD135 转基因系的行为表型发生明显变化。这是通过将 IPR2 缺失小鼠与 CMVMJD135 小鼠模型杂交，并使用成熟的与运动相关的功能测试对这些小鼠进行纵向行为特征分析来实现的。我们的结果表明，星形胶质细胞中 IPR2 的缺失不会改变 SCA3 的进展。
