Neuronal overexpression of IP3 receptor 2 is detrimental in mutant SOD1 mice

Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing progressive paralysis of the patient followed by death on average 3–5 years after diagnosis. Disease pathology is multi-factorial including the process of excitotoxicity that induces cell death by cytosolic Ca 2+ overload. In this study, we increased the neuronal expression of an endoplasmic reticulum (ER) Ca 2+ release channel, inositol 1,4,5-trisphosphate receptor 2 (IP 3 R2), to assess whether increased cytosolic Ca 2+ originating from the ER is detrimental for neurons. Overexpression of IP 3 R2 in N2a cells using a Thy1.2–IP 3 R2 construct increases cytosolic Ca 2+ concentrations evoked by bradykinin. In addition, mice generated from this construct have increased expression of IP 3 R2 in the spinal cord and brain. This overexpression of IP 3 R2 does not affect symptom onset, but decreases disease duration and shortens the lifespan of the ALS mice significantly. These data suggest that ER Ca 2+ released by IP 3 receptors may be detrimental in ALS and that motor neurons are vulnerable to impaired Ca 2+ metabolism.