The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis

Riva, Paola; Ratti, Antonia; Venturin, Marco

doi:10.2174/1567205013666160622112234

Cited by 271 publications

(180 citation statements)

References 76 publications

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“…Together with microRNAs and other small non-coding RNAs, expression alteration of lncRNAs could underlie pathogenesis of a broad range of human diseases [66]. Aside from their well-established roles in cancer [67], lncRNAs are crucial to cardiovascular [68], neurological [69], respiratory [70] and neurodegenerative [71] diseases. Among them, retinitis pigmentosa, an eye-related group of pathologies characterized by very heterogeneous genotypes but quite overlapping phenotypes, shows unusually complex molecular genetic causes, most of which are still unknown [72].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

et al. 2020

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Long non-coding RNAs (lncRNAs) are untranslated transcripts which regulate many biological processes. Changes in lncRNA expression pattern are well-known related to various human disorders, such as ocular diseases. Among them, retinitis pigmentosa, one of the most heterogeneous inherited disorder, is strictly related to oxidative stress. However, little is known about regulative aspects able to link oxidative stress to etiopathogenesis of retinitis. Thus, we realized a total RNA-Seq experiment, analyzing human retinal pigment epithelium cells treated by the oxidant agent N-retinylidene-N-retinylethanolamine (A2E), considering three independent experimental groups (untreated control cells, cells treated for 3 h and cells treated for 6 h). Differentially expressed lncRNAs were filtered out, explored with specific tools and databases, and finally subjected to pathway analysis. We detected 3,3'-overlapping ncRNAs, 107 antisense, 24 sense-intronic, four sense-overlapping and 227 lincRNAs very differentially expressed throughout all considered time points. Analyzed lncRNAs could be involved in several biochemical pathways related to compromised response to oxidative stress, carbohydrate and lipid metabolism impairment, melanin biosynthetic process alteration, deficiency in cellular response to amino acid starvation, unbalanced regulation of cofactor metabolic process, all leading to retinal cell death. The explored lncRNAs could play a relevant role in retinitis pigmentosa etiopathogenesis, and seem to be the ideal candidate for novel molecular markers and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

et al. 2020

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“…Moreover, they have been shown to serve as molecular scaffolds for nuclear compartmentalization, recruiters for chromatin‐modifying complexes, miRNA sponges and gene controllers for sequestration . Considering that lncRNAs play a diverse role in cellular networks, they have been implicated as contributing factors to many human disorders, such as cancers, neurological disorders, and CVD . It has been shown that aberrant lncRNAs expression can result in dysregulation of downstream effector molecules and consequently lead to the pathogenesis of CVD.…”

Section: Introductionmentioning

confidence: 99%

“…8 Considering that lncRNAs play a diverse role in cellular networks, they have been implicated as contributing factors to many human disorders, such as cancers, neurological disorders, and CVD. [9][10][11] It has been shown that aberrant lncRNAs expression can result in dysregulation of downstream effector molecules and consequently lead to the pathogenesis of CVD. Recent studies also showed that lncRNAs were pivotal regulators of VSMCs and ECs proliferation, migration, and cell motility.…”

Section: Introductionmentioning

confidence: 99%

LncRNA‐RP11‐714G18.1 suppresses vascular cell migration via directly targeting LRP2BP

Zhang

Zheng

et al. 2017

Immunol Cell Biol

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Atherosclerotic cardiovascular disease is considered as the leading cause of mortality and morbidity worldwide. Accumulating evidence supports an important role for long noncoding RNA (lncRNA) in the pathogenesis of atherosclerosis. Nevertheless, the role of lncRNA in atherosclerosis-associated vascular dysfunction and the underlying mechanism remain elusive. Here, using microarray analysis, we identified a novel lncRNA RP11-714G18.1 with significant reduced expression in human advanced atherosclerotic plaque tissues. We demonstrated in both human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that RP11-714G18.1 impaired cell migration, reduced the adhesion of ECs to monocytes, suppressed the neoangiogenesis, decreased apoptosis of VSMCs and promoted nitric oxide production. Mechanistically, RP11-714G18.1 could directly bind to its nearby gene LRP2BP and increased the expression of LRP2BP. Moreover, we showed that RP11-714G18.1 impaired cell migration through LRP2BP-mediated downregulation of matrix metalloproteinase (MMP)1 in both ECs and VSMCs. In atherosclerotic patients, the serum levels of LRP2BP were positively correlated with high-density lipoprotein cholesterol, but negatively correlated with cardiac troponin I. Our study suggests that RP11-714G18.1 may play an athero-protective role by inhibiting vascular cell migration via RP11-714G18.1/LRP2BP/MMP1 signaling pathway, and targeting the pathway may provide new therapeutic approaches for atherosclerosis.

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“…Like other hnRNP proteins, TDP-43 binds to nascent pre-mRNA molecules when they are released from the RNA Polymerase II (RNApol II) and regulates RNA maturation either through sequential interactions with or in collaboration/antagonism with specific RNA binding factors [3]. TDP-43 is also involved in the regulation of non-coding RNAs like miRNAs and lncRNAs [4,5]. Thanks to its ability to recognize single-stranded DNA (ssDNA) or single-stranded RNA (ssRNA) with a preferential binding to (UG)nenriched sequences [6], TDP-43 is involved in different steps of mRNA metabolism and in several mechanisms of genome integrity [7], consistent with the idea that RNA metabolism and DNA damage response (DDR) may be functionally interconnected [8].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, lines of evidence suggest that these CTFs can be produced via translation of an alternative transcript which is upregulated in ALS [20]. Recent studies proved that increased cytosolic 4 sequestration of the poly-ubiquitinated and aggregated forms of mutant TDP-43 correlates with higher levels of DNA strand breaks, activation of DDR factors such as phospho-ataxiatelangiectasia mutated (ATM), phospho-53BP1, γH2AX in SH-SY5Y lines expressing wildtype (WT) or Q331K-mutant TDP-43 [21]. TDP-43 depletion leads to increased sensitivity to various forms of DNA damage and mutation in the C-terminus glycine-rich lowcomplexity region (LC domain) associates with the loss of its nuclear function [22].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Giannini¹,

Sproviero²,

Bayona-Feliú

et al. 2020

Preprint

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TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

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The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis

Cited by 271 publications

References 76 publications

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

LncRNA‐RP11‐714G18.1 suppresses vascular cell migration via directly targeting LRP2BP

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

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