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Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP 3 receptor 2 (IP 3 R2), was detected in sporadic ALS patients. Here, we demonstrate that IP 3 R2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IP 3 R2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IP 3 R2 gene expression could be induced by lipopolysaccharide (LPS) in murine astrocytes, murine macrophages and human fibroblasts indicating that it may be a compensatory response to inflammation. Preventing this response by genetic deletion of ITPR2 from SOD1 G93A mice had a dose-dependent effect on disease duration, resulting in a significantly shorter lifespan of these mice. In addition, the absence of IP 3 R2 led to increased innate immunity, which may contribute to the decreased survival of the SOD1 G93A mice. Besides systemic inflammation, IP 3 R2 knockout mice also had increased IFNγ, IL-6 and IL1α expression. Altogether, our data indicate that IP 3 R2 protects against the negative effects of inflammation, suggesting that the increase in IP 3 R2 expression in ALS patients is a protective response.

Genetic ablation of IP3receptor 2 increases cytokines and decreases survival ofSOD1G93Amice

Genetic ablation of IP₃receptor 2 increases cytokines and decreases survival ofSOD1^G93Amice