A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease <i>substantia nigra</i>

Simchovitz, Alon; Hanan, Mor; Yayon, Nadav; Lee, Songhua; Bennett, Estelle R.; Greenberg, David; Kadener, Sebastián; Soreq, Hermona

doi:10.1111/acel.13115

Cited by 46 publications

(56 citation statements)

References 41 publications

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“…Disease age of onset in families with mutations in these genes is between 20 and 50, considerably earlier than 65 years of age, the typical onset age for the sporadic forms of the disease. Additionally, PD involves massive changes in RNA metabolism (La Cognata et al , ), both in brain neurons (Liu et al , ) and in patients’ leukocytes (Soreq et al , , , ; Simchovitz et al , ), but contributions of circular RNAs (circRNAs) to PD risks have so far remained unexplored.…”

Section: Introductionmentioning

confidence: 99%

A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

et al. 2020

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Circular RNAs (circRNAs) are brain‐abundant RNAs of mostly unknown functions. To seek their roles in Parkinson's disease (PD), we generated an RNA sequencing resource of several brain region tissues from dozens of PD and control donors. In the healthy substantia nigra (SN), circRNAs accumulate in an age‐dependent manner, but in the PD SN this correlation is lost and the total number of circRNAs reduced. In contrast, the levels of circRNAs are increased in the other studied brain regions of PD patients. We also found circSLC8A1 to increase in the SN of PD individuals. CircSLC8A1 carries 7 binding sites for miR‐128 and is strongly bound to the microRNA effector protein Ago2. Indeed, RNA targets of miR‐128 are also increased in PD individuals, suggesting that circSLC8A1 regulates miR‐128 function and/or activity. CircSLC8A1 levels also increased in cultured cells exposed to the oxidative stress‐inducing agent paraquat but were decreased in cells treated with the neuroprotective antioxidant regulator drug Simvastatin. Together, our work links circSLC8A1 to oxidative stress‐related Parkinsonism and suggests further exploration of its molecular function in PD.

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Section: Introductionmentioning

confidence: 99%

A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

et al. 2020

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“…Moreover, the inflammation regulator NFkB1 was only increased under SARS-CoV-2 infection ( Figure 2B ). Both DANCR and the sepsis-related neuroprotective lncRNA NEAT1, which initiates and maintains the membrane-less organelle of nuclear paraspeckles ( 30 , 33 , 39 ), were suppressed in SARS-CoV-2 infected cells ( Figure 2C ) (see corresponding Resource in Supplementary Table 1 for the full list of lncRNAs changed in NHBE and A549 cells infected with SARS-CoV-2, in NHBE cells infected with pandemic H1N1, and in lung inflammatory samples). Together, these observations indicated that inter-related changes in DANCR, NEAT1, and NFkB1 might play specific regulatory roles in the natural history of SARS-CoV-2 infection.…”

Section: Resultsmentioning

confidence: 99%

“…The lncRNA-mediated “overwatch” may avert cytokine storms characteristic of sepsis; and prevent detrimental life-threatening states which may develop where these and other mediators fail to harness overwhelming inflammation ( 35 ). Correspondingly, changes in inflammation-related ncRNAs, coupled with modified cholinergic surveillance, are evident in infectious, neuro-inflammatory and other conditions, including brain ramifications ( 30 , 37 , 119 , 128 – 130 ). These include, for instance, the activity of the brain’s miR-218 in conjunction with cholinergic machinery in the context of amyotrophic lateral sclerosis (ALS) ( 131 ).…”

Section: Discussionmentioning

confidence: 99%

The Neat Dance of COVID-19: NEAT1, DANCR, and Co-Modulated Cholinergic RNAs Link to Inflammation

2020

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The COVID-19 pandemic exerts inflammation-related parasympathetic complications and post-infection manifestations with major inter-individual variability. To seek the corresponding transcriptomic origins for the impact of COVID-19 infection and its aftermath consequences, we sought the relevance of long and short non-coding RNAs (ncRNAs) for susceptibility to COVID-19 infection. We selected inflammation-prone men and women of diverse ages among the cohort of Genome Tissue expression (GTEx) by mining RNA-seq datasets from their lung, and blood tissues, followed by quantitative qRT-PCR, bioinformatics-based network analyses and thorough statistics compared to brain cell culture and infection tests with COVID-19 and H1N1 viruses. In lung tissues from 57 inflammation-prone, but not other GTEx donors, we discovered sharp declines of the lung pathology-associated ncRNA DANCR and the nuclear paraspeckles forming neuroprotective ncRNA NEAT1. Accompanying increases in the acetylcholine-regulating transcripts capable of controlling inflammation co-appeared in SARS-CoV-2 infected but not H1N1 influenza infected lung cells. The lung cells-characteristic DANCR and NEAT1 association with inflammation-controlling transcripts could not be observed in blood cells, weakened with age and presented sex-dependent links in GTEx lung RNA-seq dataset. Supporting active involvement in the inflammatory risks accompanying COVID-19, DANCR’s decline associated with decrease of the COVID-19-related cellular transcript ACE2 and with sex-related increases in coding transcripts potentiating acetylcholine signaling. Furthermore, transcription factors (TFs) in lung, brain and cultured infected cells created networks with the candidate transcripts, indicating tissue-specific expression patterns. Supporting links of post-infection inflammatory and cognitive damages with cholinergic mal-functioning, man and woman-originated cultured cholinergic neurons presented differentiation-related increases of DANCR and NEAT1 targeting microRNAs. Briefly, changes in ncRNAs and TFs from inflammation-prone human lung tissues, SARS-CoV-2-infected lung cells and man and woman-derived differentiated cholinergic neurons reflected the inflammatory pathobiology related to COVID-19. By shifting ncRNA differences into comparative diagnostic and therapeutic profiles, our RNA-sequencing based Resource can identify ncRNA regulating candidates for COVID-19 and its associated immediate and predicted long-term inflammation and neurological complications, and sex-related therapeutics thereof. Our findings encourage diagnostics of involved tissue, and further investigation of NEAT1-inducing statins and anti-cholinergic medications in the COVID-19 context.

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“…However, NEAT1 expression has been shown to be neuroprotective, since the interference-mediated depletion of NEAT1 aggravated death in the cells exposed to paraquat in a LRRK2-mediated manner. A study focused on identifying deregulated lncRNAs in the substantia nigra of PD patients described a pronounced increase in the Long Intergenic Non-Protein Coding RNA, p53-Induced Transcript, LINC-PINT, that was also observed in other models of PD and other neurodegenerative conditions [203]. Experimentally, the depletion of LINC-PINT exacerbated the death of cultured neuronal cells exposed to OS, suggesting a neuroprotective role of this transcript in diverse neurodegenerative disorders.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

et al. 2020

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Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

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A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

Cited by 46 publications

References 41 publications

A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

The Neat Dance of COVID-19: NEAT1, DANCR, and Co-Modulated Cholinergic RNAs Link to Inflammation

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

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