Ethel Percy Andrus Gerontology Center, Davis School of Gerontology, University of Southern California, 3715 McClintock Ave., Los Angeles, CA 90089-0191, USA.
FASEB J. 2011 Oct;25(10):3306-11. doi: 10.1096/fj.11-185728. Epub 2011 Jun 16.
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.
长期以来，人们一直怀疑慢性压力会加重甚至导致疾病。我们现在提出，RCAN1 基因（它可以产生几种 RCAN1 蛋白同工型）可能至少部分负责这一现象。我们回顾了表明 RCAN1 蛋白可以被多种应激诱导的数据，并提出了新的数据，也表明心理社会/情绪应激会诱导 RCAN1 的表达。我们进一步表明，过度表达 RCAN1-1L 蛋白的转基因小鼠表现出过度磷酸化 tau 蛋白（AT8 抗体）的积累，这是神经原纤维缠结和阿尔茨海默病中所见的神经退行性变的早期前体。我们提出，尽管 RCAN1 基因的瞬时诱导可能会保护细胞免受急性应激，但持续的应激可能导致 RCAN1 的慢性过表达，从而导致严重的副作用。RCAN1 蛋白的慢性升高可能会促进或加重各种疾病，包括阿尔茨海默病等 tau 病。我们提出，应激导致这些疾病的机制涉及 RCAN1 蛋白对钙调神经磷酸酶的抑制和对 GSK-3β的诱导。钙调神经磷酸酶的抑制和 GSK-3β的诱导都有助于磷酸化 tau 的积累、神经原纤维缠结的形成以及最终的神经退行性变。
