Do RCAN1 proteins link chronic stress with neurodegeneration?

It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3β by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3β contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.