Calbindin-D9k is a novel risk gene for neurodegenerative disease

Background: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D9k (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown. Methods: We used CaBP-9k knockout (KO) mice to investigate the roles of these proteins in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Results: We found that the brains of CaBP-9k KO mice have increased APP/β-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these calbindins had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related gene expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice. Conclusion: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.