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.

Keywords: (mitochondrial) adenine nucleotide transporter; ANT; Alzheimer disease; Free radicals; GSK-3β; Mitochondria; Neurodegeneration; Oxidative stress; RCAN1; glycogen synthase kinase-3β; mitochondrial permeability transition pore; mtPTP; regulator of calcineurin 1.

Fig. 1

Possible mechanisms by which long-term stress may cause neurodegeneration via chronic RCAN1 induction. Multiple forms of chronic stress can induce prolonged synthesis of RCAN1 proteins at high levels. Although both RCAN1-1 and RCAN1-4 protein levels can be increased by stress, the mechanisms by which protein levels are elevated seem to be different, and only RCAN1-1 is induced by glucocorticoids [29,30]. Chronically elevated levels of RCAN1-L cause long-term inhibition of calcineurin and increased activity of GSK-3β, both of which can lead (over time) to the accumulation of hyperphosphorylated tau protein. The accumulation of hyperphosphorylated tau may (eventually) cause the formation of neurofibrillary tangles, which promote neurodegeneration. On the other hand, RCAN1-1L can bind to the mitochondrial adenine nucleotide translocator (ANT) and inhibit its ADP/ATP transporting activity, which can lead to reduced cellular ATP levels. RCAN1-1L binding to ANT can also cause opening of the mitochondrial permeability transition pore (mtPTP). Both mtPTP opening and decreased ATP levels can initiate mitochondrial autophagy (“mitophagy”) and may even lead to apoptotic and/or necrotic cell death.