RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration

Porta, Sílvia; Serra, Selma A.; Huch, Meritxell; Valverde, Miguel A.; Llorens, Franc; Estivill, Xavier; Arbonés, María L.; Martı́, Eulàlia

doi:10.1093/hmg/ddm049

Cited by 85 publications

(82 citation statements)

References 60 publications

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“…Problems occur when production of ROS exceeds their elimination by the antioxidant protection systems or when the latter are damaged. This imbalance between cellular production of ROS and the inability of cells to defend against their effects is called oxidative stress, which is a major factor in the pathogenesis of neuronal damage and is involved in acute and chronic CNS injury [36] . In addition, an important mechanism of O 2 ·-toxicity is its direct oxidation and resulting inactivation of iron-sulfur (Fe-S) proteins, leading to the release of iron.…”

Section: Excitotoxicity and Oxidative Stressmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glutamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.

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Section: Excitotoxicity and Oxidative Stressmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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“…44) Furthermore, oxidative stress induces RCAN1 expression in primary neurons. 45) Aβ causes neuronal cell death by enhancing oxidative stress and disrupting cellular calcium homeostasis in the AD brain. 46) Transient overexpression of RCAN1 induced by perturbation of the calcineurin-NFAT negative feedback loop might protect cells against oxidative stress and Ca 2+ overload, leading to chronic RCAN1 overexpression, thereby exacerbating AD pathology in a calcineurin-dependent or -independent manner.…”

Section: )mentioning

confidence: 99%

Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer’s Disease

Kinjo

Kimura

Mori

et al. 2016

Biological & Pharmaceutical Bulletin

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Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.Key words Alzheimer's disease; Down syndrome; calcineurin; neprilysin; nuclear factor of activated T cell (NFAT); tau Down syndrome (DS) is the most frequent congenital chromosomal disorder, and is primarily caused by an extra copy of chromosome 21. The incidence of DS, approximately one in 600-800 live births, increases with maternal age.1,2) The characteristic physical features of the disease include a flattened face and nose, small head, ears and mouth, wide, short hands with short fingers, dry skin, and decreased or poor muscle tone. Children with DS are at increased risk of complications, including heart defects, hearing and vision problems, obesity, leukemia, and other conditions. 3-5) DS patients in middle age are more susceptible to the development of Alzheimer's disease (AD), 6,7) whereas most cancers are rare in people with DS, in whom overall cancer mortality is below 10% of that in the general population. 8)Vascular endothelial growth factor (VEGF) plays a central role in tumor development.9,10) VEGF and the calcineurinnuclear factor of activated T cells (NFAT) signaling pathway regulates cancer metastasis.9) The Ca 2+ /calmodulin-dependent serine/threonine phosphatase calcineurin dephosphorylates NFAT in the cytoplasm, leading to its nuclear translocation and activation.9,11,12) Dual specificity tyrosine-phosphorylationregulated kinase 1A (DYRK1A) phosphorylates NFAT in the nucleus, leading to its cytoplasmic translocation and inactivation.9,12) Calcineurin is negatively regulated by the DS critical region protein regulator of calcineurin 1 (RCAN1) in the cytoplasm. 9,12) The genes for both DYRK1A and RCAN1 are located on chromosome 21. The calcineurin-NFAT signaling pathway is perturbed by the increased dosage of DYRK1A and RCAN1 in DS pa...

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“…RCAN1 has therefore been proposed as a candidate protein responsible for mental retardation in DS. RCAN1 has also been implicated in oxidative stress and exocytosis (23,24).…”

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confidence: 99%

Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

Jung

Park

Ryu

et al. 2011

Journal of Biological Chemistry

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RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration

Cited by 85 publications

References 60 publications

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer’s Disease

Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

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