Neurodegeneration as an RNA disorder

Johnson, Rory; Noble, Wendy; Tartaglia, Gian Gaetano; Buckley, Noel J.

doi:10.1016/j.pneurobio.2012.09.006

Cited by 53 publications

(39 citation statements)

References 316 publications

(340 reference statements)

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“…Due in part to the gains in knowledge of the human genome, made possible by next-generation sequencing and similar techniques, there is increasing evidence of the involvement of miRNAs in the development of the central nervous system and in neurodegeneration[10]. Recent reports have shown that aberrant miRNA expression contributes to neurodegeneration, and that NDDs may be considered as a class of RNA disorders [11, 12]. The failures of a number of surgical and pharmacological treatments for NDDs highlight the need for novel therapeutic approaches to regulate several targets and molecular pathways.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy

Karnati

Panigrahi

Gutti

et al. 2015

JAD

110

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MicroRNAs (miRNAs) are endogenous, ~22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with AD, PD and frontotemporal dementia (FTD). A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention.

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Section: Neurodegenerative Diseasesmentioning

confidence: 99%

miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy

Karnati

Panigrahi

Gutti

et al. 2015

JAD

110

View full text Add to dashboard Cite

show abstract

“…This would have been impossible in any other transgenic mouse model that uses cDNA to express the mutant ataxin-2. In fact, considering the increasing relevance given to RNA-related mechanisms of toxicity in neurodegenerative diseases, the BAC-Q72 is the most adequate model to study these phenomena in SCA2 (Johnson et al, 2012; Tan et al, 2012; Cleary and Ranum, 2013; Ramaswami et al, 2013). Besides this, the mice also displayed a moderate ataxic phenotype at 16 weeks, with impairments in the accelerated rotarod, which worsened in a progressive manner.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies have highlighted the contribution of non-coding RNA molecules, such as anti-sense and long non-coding transcripts, to the pathophysiology of polyQ and other neurodegenerative disorders (Moseley et al, 2006; Ladd et al, 2007; de Mezer et al, 2011). The mechanisms of RNA toxicity in neurodegeneration have been extensively reviewed elsewhere (Johnson et al, 2012; Salta and De Strooper, 2012; Tan et al, 2012) and include the sequestration of RNA-binding proteins, the production of mutant repeat RNA molecules by anti-sense transcription and the modulation of mutated genes by miRNAs. In SCA2, bidirectional transcription of the ATXN2 gene has been recently reported, with the production of a neurotoxic anti-sense transcript ( ATXN2-AS ) as a consequence (Li et al, 2016).…”

Section: Disease Mechanisms Of Sca2mentioning

confidence: 99%

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

et al. 2016

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide.

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“…Since one miRNA can alter the expression of hundreds of genes, there have been views that NDDs are RNA disorders [63]. Specific miRNAs associated with PD, AD, HD, and ALS are known [64].…”

Section: Mirnas As Factors Of Neuroepigenetics and Biomarkers For Neumentioning

confidence: 99%

Neurogenetics and neuroepigenetics

2015

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Behavioral genetics or "Neurogenetics," is based on the evolutionary ideas of T. Dobzhansky on brain development and behavior. It continues with the "experimental genetics of higher nervous activity" of I. Pavlov and uses a comparative approach in the study of heredity and variation in behavioral manifestations, from Protozoa to humans. The study of the classical Pavlovian conditioned reflex in mutant Drosophila helped to identify the main types of memory and their evolutionary conservatism. Long term memory defects are caused by mutations of the same genes as in mental retardation in humans, when signaling cascades inter secting with the cAMP dependent pathway are damaged. The cascade of actin remodeling is also among these. The key enzyme, LIM kinase 1, controls cognitive manifestations of the "genomic disease" Williams deletion syndrome. Its study resulted in the recognition of neuroepigenetics as an interface between the genome and environmental influences. Epigenetic factors of "variability"-DNA methylation, histone acetylation, and miRNA regulation-do not change the structure of the gene but its manifestations. Certain miRNAs have already been considered to be both biomarkers for neurodegenerative diseases and factors of the transgenerational transmission of the behaviorial properties of ancestors who experienced stress from adverse environmental influences.

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Neurodegeneration as an RNA disorder

Cited by 53 publications

References 316 publications

miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy

miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

Neurogenetics and neuroepigenetics

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