Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease

Abstract

The RCAN1 gene encodes three different protein isoforms: RCAN1-4, RCAN1-1L, and RCAN1-1S. RCAN1-1L is the RCAN1 isoform predominantly expressed in human brains. RCAN1 proteins have been shown to regulate various other proteins and cellular functions, including calcineurin, glycogen synthase kinase-3β (GSK-3β), the mitochondrial adenine nucleotide transporter (ANT), stress adaptation, ADP/ATP exchange in mitochondria, and the mitochondrial permeability transition pore (mtPTP). The effects of increased RCAN1 gene expression seem to depend both on the specific RCAN1 protein isoform(s) synthesized and on the length of time the level of each isoform is elevated. Transiently elevated RCAN1-4 and RCAN1-1L protein levels, lasting just a few hours, can be neuroprotective under acute stress conditions, including acute oxidative stress. We propose that, by transiently inhibiting the phosphatase calcineurin, RCAN1-4 and RCAN1-1L may reinforce and extend protective stress-adaptive cell responses. In contrast, prolonged elevation of RCAN1-1L levels is associated with the types of neurodegeneration observed in several diseases, including Alzheimer disease and Down syndrome. RCAN1-1L levels can also be increased by multiple chronic stresses and by glucocorticoids, both of which can cause neurodegeneration. Although increasing levels of RCAN1-1L for just a few months has no overtly obvious neurodegenerative effect, it does suppress neurogenesis. Longer term elevation of RCAN1-1L levels (for at least 16 months), however, can lead to the first signs of neurodegeneration. Such neurodegeneration may be precipitated by (RCAN1-1L-mediated) prolonged calcineurin inhibition and GSK-3β induction/activation, both of which promote tau hyperphosphorylation, and/or by (RCAN1-1L-mediated) effects on the mitochondrial ANT, diminished ATP/ADP ratio, opening of the mtPTP, and mitochondrial autophagy. We propose that RCAN1-1L operates through various molecular mechanisms, primarily dependent upon the length of time protein levels are elevated. We also suggest that models analyzing long-term RCAN1 gene overexpression may help us to understand the molecular mechanisms of neurodegeneration in diseases such as Alzheimer disease, Down syndrome, and possibly others.

The calcineurin antagonist RCAN1-4 is induced by exhaustive exercise in rat skeletal muscle

“…An increase in modulatory calcineurin-interacting protein 1(MCIP1) has been reported in human skeletal muscle during recovery from eccentric exercise [48]. RCAN1-4 is known to be a cytoprotective element in the adaptive response to oxidative stress [13,14], whereas altered RCAN1-1 expression has been associated with pathologies [1, [8][9][10][11].…”

“…Chronic RCAN1-1 overexpression is associated with pathophysiological conditions such as Down's syndrome (1.9 -fold in fetal brain tissue and up to 3-fold within the adult hippocampus) [6,7] , cancer, cardiac disorders and Alzheimer's' disease. [1,[8][9][10][11]. Conversely RCAN1-1L underexpression may be associated with the severity of symptoms in patients with Huntington's disease [12].…”

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].…”

Protein Profiles Associated With Context Fear Conditioning and Their Modulation by Memantine

“…Memantine did not affect the distribution of CaNA, but in NLϩM, CaNA increased in both the membrane and nuclear fractions. RCAN1 is an inhibitor of CaN and it is increased in brains of AD patients (60) and has been proposed to have roles in increased Tau phosphorylation and in neurodegeneration (61,62). In NL, RCAN1 is increased in the membrane fraction, while memantine treatment produced increases in RCAN1 in all three fractions.…”