RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis

• Published in: PloS one Vol. 9; no. 4; p. e95471
• Main Authors: Sun, Xiulian, Wu, Yili, Herculano, Bruno, Song, Weihong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Analysis; Animals; Apoptosis; Apoptosis - genetics; Base Sequence; Biology and Life Sciences; Brain research; Calcineurin; Calcium; Calcium - metabolism; Caspase; Caspase 3 - metabolism; Caspase-3; Cell Line; Cortex; Down syndrome; Down's syndrome; Feedback loops; Gene expression; Gene regulation; Genetic aspects; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Isoforms; Kinases; Laboratories; Medicine and Health Sciences; Molecular Sequence Data; Muscle Proteins - genetics; Muscle Proteins - metabolism; Negative feedback; Neurodegenerative diseases; Neurons; Neurons - cytology; Neurons - metabolism; Neurotoxins - toxicity; NF-AT protein; NFATC Transcription Factors - metabolism; Overloading; Oxidative stress; Pathogenesis; Patients; Promoter Regions, Genetic - genetics; Protein Isoforms - genetics; Protein Isoforms - metabolism; Risk factors; Signal transduction; Signal Transduction - genetics; Signaling; Transcription; Transcription, Genetic; Up-Regulation - genetics; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095471

Down Syndrome (DS) patients develop characteristic Alzheimer's Disease (AD) neuropathology after their middle age. Prominent neuronal loss has been observed in the cortical regions of AD brains. However, the underlying mechanism leading to this neuronal loss in both DS and AD remains to be elucidated. Calcium overloading and oxidative stress have been implicated in AD pathogenesis. Two major isoforms of regulator of calcineurin 1 (RCAN1), RCAN1.1 and RCAN1.4, are detected in human brains. In this report we defined the transcriptional regulation of RCAN1.1 and RCAN1.4 by two alternative promoters. Calcium overloading upregulated RCAN1.4 expression by activating RCAN1.4 promoter through calcineurin-NFAT signaling pathway, thus forming a negative feedback loop in isoform 4 regulation. Furthermore, RCAN1.4 overexpression exacerbated calcium overloading-induced neuronal apoptosis, which was mediated by caspase-3 apoptotic pathway. Our results suggest that downregulating RCAN1.4 expression in neurons could be beneficial to AD patients.