The long non-coding RNA NEAT1 is elevated in polyglutamine repeat expansion diseases and protects from disease gene-dependent toxicities

Cheng, Congsheng; Spengler, Ryan M; Keiser, Megan S.; Monteys, Alejandro Mas; Rieders, Julianne; Ramachandran, Shyam; Davidson, Beverly L.

doi:10.1093/hmg/ddy331

Cited by 31 publications

(34 citation statements)

References 49 publications

(69 reference statements)

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“…It is intriguing to speculate a correlation between MeCP2 interaction with paraspeckle lncRNA, NEAT1, which can scaffold Drosha and DGCR8 to peripheral paraspeckle proteins, resulting in the regulation of miRNA biogenesis ( Jiang et al, 2017 ). MeCP2 is known to bind the long isoform of NEAT1 in the brain (see below) ( Cheng et al, 2018 ).…”

Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

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Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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“… [ 111 , 115 ] Huntington's disease (HD) Up (microarrays, RNA-Seq, qRT-PCR) Human : brain (caudate) Rodent: R6/2 mouse model; brain Protective MeCP2 protein represses NEAT1_2 under normal conditions; in HD, MeCP2 becomes downregulated which leads to NEAT1_2 accumulation. [ [118] , [119] , [120] , [121] , [122] , [123] ] Parkinson's disease (PD) Up (microarrays) Human: brain (substantia nigra) Rodent: MPTP mouse model; midbrain Detrimental NEAT1 stabilises the PD-associated protein PINK1 and promotes PINK1-mediated autophagy. [ 127 , 128 ] Alzheimer's disease (AD) Up (microarrays; RNA-Seq, qRT-PCR) Human: hippocampus, entorhinal cortex, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus Rodent : N/A Protective NEAT1 positively regulates miR-15/107 which decreases CDK5R1 expression.…”

Section: Neat1/paraspeckles Are Dysregulated In Neurodegenerative Dismentioning

confidence: 99%

“…RNA-Seq analysis of prefrontal cortex from 20 HD and 49 control individuals also found moderate, ∼20% upregulation of NEAT1 in HD [ 121 ]. A recent study, specifically focused on NEAT1_2, detected 3-fold increase of this isoform in the brain of HD patients by qRT-PCR [ 122 ]. Consistently, NEAT1 is overexpressed in the brains of R6/2 transgenic mice, a well-established HD model [ 120 , 123 ].…”

Section: Neat1/paraspeckles Are Dysregulated In Neurodegenerative Dismentioning

confidence: 99%

“…Consistently, NEAT1 is overexpressed in the brains of R6/2 transgenic mice, a well-established HD model [ 120 , 123 ]. In cell models of HD, overexpressing mutant huntingtin, exogenous NEAT1_1 protected cells against H 2 O 2 -induced toxicity [ 120 ], whereas NEAT1_2 knockdown decreased cell survival [ 122 ].…”

Section: Neat1/paraspeckles Are Dysregulated In Neurodegenerative Dismentioning

confidence: 99%

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NEAT1 and paraspeckles in neurodegenerative diseases: A missing lnc found?

Williams

Shelkovnikova

2018

Non-coding RNA Research

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Neurodegenerative diseases are among the most common causes of disability worldwide. Although neurodegenerative diseases are heterogeneous in both their clinical features and the underlying physiology, they are all characterised by progressive loss of specific neuronal populations. Recent experimental evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the CNS in health and disease. Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is an abundant, ubiquitously expressed lncRNA, which forms a scaffold for a specific RNA granule in the nucleus, or nuclear body, the paraspeckle. Paraspeckles act as molecular hubs for cellular processes commonly affected by neurodegeneration. Transcriptomic analyses of the diseased human tissue have revealed altered NEAT1 levels in the CNS in major neurodegenerative disorders as well as in some disease models. Although it is clear that changes in NEAT1 expression (and in some cases, paraspeckle assembly) accompany neuronal damage, our understanding of NEAT1 contribution to the disease pathogenesis is still rudimentary. In this review, we have summarised the available knowledge on NEAT1 involvement in the molecular processes linked to neurodegeneration and on NEAT1 dysregulation in this type of disease, with a special focus on amyotrophic lateral sclerosis. The goal of this review is to attract the attention of researchers in the field of neurodegeneration to NEAT1 and paraspeckles.

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“…Since TUG1 also binds to the PRC2 epigenetic regulatory complex of genes, TUG1 upregulation may be involved in multiple molecular pathways in the human HD brain [30]. Furthermore, both MEG3 and NEAT1 are upregulated in HD mouse R6/2 cortex, and reducing MEG3 and NEAT1 expression modulates mHTT aggregates and TP53 expression through unknown mechanisms [27][28][29]. RPS20P22 regulates RPS20 expression, and the decrease of RPS20P22 leads to accumulation of p53 in HD brain [25].…”

Section: Ncrnas In the Regulation Of Hd-associated Apoptosismentioning

confidence: 99%

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

2020

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Recent transcriptome analyses have revealed that noncoding RNAs (ncRNAs) are broadly expressed in mammalian cells and abundant in the CNS, with tissue and cell type-specific expression patterns. Moreover, ncRNAs have been found to intricately and dynamically regulate various signaling pathways in neurodegeneration. As such, some antisense transcripts and microRNAs are known to directly affect neurodegeneration in disease contexts. The functions of ncRNAs in pathogenesis are unique for each disorder, as are the pertinent networks of ncRNA/miRNA/ mRNA that mediate these functions. Thus, further understanding of ncRNA biogenesis and effects might aid the discovery of diagnostic biomarkers or development of effective therapeutics for neurodegenerative disorders. Here, we review the ncRNAs that have so far been identified in major neurodegenerative disease etiology and the mechanisms that link ncRNAs with disease-specific phenotypes, such as HTT aggregation in HD, α-synuclein in PD, and Aβ plaques and hyperphosphorylated Tau in AD. We also summarize the known lncRNA/miRNA/mRNA networks that participate in neurodegenerative diseases, and we discuss ncRNA-related treatments shown to delay disease onset and prolong lifespan in rodent models.

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The long non-coding RNA NEAT1 is elevated in polyglutamine repeat expansion diseases and protects from disease gene-dependent toxicities

Cited by 31 publications

References 49 publications

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

NEAT1 and paraspeckles in neurodegenerative diseases: A missing lnc found?

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

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