Conversely, activation of XBP1 downregulates the ryanodine calcium channel and prevents the accumulation of free calcium in the cytosol during ER stress.46 Ryanodine receptors (RyRs) are major ion channel proteins responsible for ER calcium release and their dysregulation is implicated in neurodengerative diseases such as Alzheimer's disease. This evidence concerns the gene XBP1 and early-onset autosomal dominant Alzheimer disease.