Do RCAN1 proteins link chronic stress with neurodegeneration?

Abstract

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.

RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer’s disease

“…Together with the report that RCAN1 levels increase in the human brain with normal aging [7], these findings suggest a role for chronic RCAN1 overexpression in the age-related progression of AD. RCAN1.1L is the predominant isoform in the brain, and it is overexpression of this isoform in AD and DS brains that has been reported and shown recently to promote AD-like pathophysiology [12, 13, 39, 46, 61]. Interestingly, however, RCAN1.1L overexpression was shown to protect cells initially but facilitated apoptosis after long-term overexpression, whereas both short- and long-term overexpression of the RCAN1.1S isoform facilitated apoptosis [61], suggesting RCAN1.1S may be particularly toxic.…”

Chronic Expression of RCAN1-1L Protein Induces Mitochondrial Autophagy and Metabolic Shift from Oxidative Phosphorylation to Glycolysis in Neuronal Cells

“…RCAN1-1L can be induced by multiple stresses as well as various human diseases (4). Depending on the condition, it can be induced severalfold (by some stressors) or just 2-3-fold (as in Down syndrome and Alzheimer disease).…”

“…To distinguish between these possibilities, we designed experiments in which autophagosome clearance was prevented using inhibitors of lysosomal proteolysis (20 mM NH 4 Cl ϩ 100 M leupeptin). As previously, LC3-II levels were increased ϳ2-fold at 9 h after transfection (Fig.…”

Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer׳s disease

“…RCAN1 is expressed in many brain regions [34] and is involved in adaptive responses to oxidative stress [35]. Chronic activation of RCAN promotes neurodegeneration [36,37]. RCAN1 inhibits calcineurin, a p-Tau phosphatase, leading to Tau hyperphosphorylation [38].…”