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

Abstract Aging is the largest risk factor for Alzheimer’s disease (AD). Patients with Down syndrome (DS) develop symptoms consistent with early-onset AD, suggesting that overexpression of chromosome 21 genes such as Regulator of Calcineurin 1 (RCAN1) plays a role in AD pathogenesis. RCAN1 levels are increased in the brain of DS and AD patients but also in the human brain with normal aging. RCAN1 has been implicated in several neuronal functions, but whether its increased expression is correlative or causal in the aging-related progression of AD remains elusive. We show that brain-specific overexpression of the human RCAN1.1S isoform in mice promotes early age-dependent memory and synaptic plasticity deficits, tau pathology, and dysregulation of dynamin-related protein 1 (DRP1) activity associated with mitochondrial dysfunction and oxidative stress, reproducing key AD features. Based on these findings, we propose that chronic RCAN1 overexpression during aging alters DRP1-mediated mitochondrial fission and thus acts to promote AD-related progressive neurodegeneration.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT. Introduction Rett syndrome (RTT) is a progressive neurodevelopmental disorder. It primarily affects females, who show the first obvious symptoms within 6–18 months after birth. Among the characteristics are a regression of mental ...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Publication date: Available online 4 January 2019Source: Neuroscience &Biobehavioral ReviewsAuthor(s): Rosa Anna Vacca, Sweta Bawari, Daniela Valenti, Devesh Tewari, Seyed Fazel Nabavi, Samira Shirooie, Archana N. Sah, Mariateresa Volpicella, Nady Braidy, Seyed Mohammad NabaviAbstractDown syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal loss, anomalous glutamatergic transmission and N-methyl...
Source: Neuroscience and Biobehavioral Reviews - Category: Neuroscience Source Type: research
When Noah Shulman was born a few days after Christmas 2016, his parents Kristelle and Evan had no reason to worry about him. The pregnancy went smoothly, and so did the birth. But within a few days of taking his first breath, Noah began to struggle. He wasn’t feeding, so he started losing weight. He was also lethargic. Several pediatricians reassured the Shulmans that they were probably just overly sensitive to Noah’s symptoms because Kristelle is a nurse and Evan is a physician assistant–a case of first-time-parent-white-coat syndrome. “They kind of dismissed us as neurotic parents,” says Eva...
Source: TIME: Science - Category: Science Authors: Tags: Uncategorized fertility Research Source Type: news
RIP140/PGC-1α axis involved in vitamin A-induced neural differentiation by increasing mitochondrial function. Artif Cells Nanomed Biotechnol. 2018 Mar 07;:1-11 Authors: Mu Q, Yu W, Zheng S, Shi H, Li M, Sun J, Wang D, Hou X, Liu L, Wang X, Zhao Z, Liang R, Zhang X, Dong W, Zeng C, Guo J Abstract Vitamin A deficiency and mitochondrial dysfunction are both associated with neural differentiation-related disorders, such as Alzheimer's disease (AD) and Down syndrome (DS). The mechanism of vitamin A-induced neural differentiation and the notion that vitamin A can regulate the morphology and function of...
Source: Artificial Cells, Nanomedicine and Biotechnology - Category: Biotechnology Tags: Artif Cells Nanomed Biotechnol Source Type: research
Conclusions: RCAN1 helps maintain a more interconnected mitochondrial network and maintaining appropriate RCAN1 levels is important to human health and disease. PMID: 29362227 [PubMed - as supplied by publisher]
Source: Circulation Research - Category: Cardiology Authors: Tags: Circ Res Source Type: research
This article is protected by copyright. All rights reserved. PMID: 29094385 [PubMed - as supplied by publisher]
Source: Clinical and Experimental Pharmacology and Physiology - Category: Drugs & Pharmacology Authors: Tags: Clin Exp Pharmacol Physiol Source Type: research
In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, P
Source: The International Journal of Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Int J Biochem Cell Biol Source Type: research
Publication date: Available online 20 September 2017 Source:Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Author(s): Daniela Valenti, Leonardo Rossi, Domenico Marzulli, Francesco Bellomo, Domenico De Rasmo, Anna Signorile, Rosa Anna Vacca Functional and structural damages to mitochondria have been critically associated with the pathogenesis of Down syndrome (DS), a human multifactorial disease caused by trisomy of chromosome 21 and associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, we demonstrated in neural progenitor cells (NPCs) isolated from the h...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
Abstract Mitochondria play a pivotal role in cellular energy-generating processes and are considered master regulators of cell life and death fate. Mitochondrial function integrates signalling networks in several metabolic pathways controlling neurogenesis and neuroplasticity. Indeed, dysfunctional mitochondria and mitochondrial-dependent activation of intracellular stress cascades are critical initiating events in many human neurodegenerative or neurodevelopmental diseases including Down syndrome (DS). It is well established that trisomy of human chromosome 21 can cause DS. DS is associated with neurodevelopmenta...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research
mTOR IN DOWN SYNDROME: ROLE in Aß and TAU NEUROPATHOLOGY and TRANSITION to ALZHEIMER DISEASE-LIKE DEMENTIA. Free Radic Biol Med. 2017 Aug 11;: Authors: Di Domenico F, Tramutola A, Foppoli C, Head E, Perluigi M, Butterfield DA Abstract The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studie...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research
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