NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress

Abstract

Recent reports attribute numerous regulatory functions to the nuclear paraspeckle‐forming long non‐coding RNA, nuclear enriched assembly transcript 1 (NEAT1), but the implications of its involvement in Parkinson's disease (PD) remain controversial. To address this issue, we assessed NEAT1 expression levels and cell type patterns in the substantia nigra (SN) from 53 donors with and without PD, as well as in interference tissue culture tests followed by multiple in‐house and web‐available models of PD. PCR quantification identified elevated levels of NEAT1 expression in the PD SN compared with control brains, an elevation that was reproducible across a multitude of disease models. In situ RNA hybridization supported neuron‐specific formation of NEATl‐based para‐speckles at the SN and demonstrated coincreases of NEAT1 and paraspeckles in cultured cells under paraquat (PQ)‐induced oxidative stress. Furthermore, neuroprotective agents, including fenofibrate and simvastatin, induced NEAT1 up‐regulation, whereas RNA interference—mediated depletion of NEAT1 exacerbated death of PQ‐exposed cells in a leucine‐rich repeat kinase 2‐mediated manner. Our findings highlight a novel protective role for NEAT1 in PD and suggest a previously unknown mechanism for the neuroprotective traits of widely used preventive therapeutics.—Simchovitz, A., Hanan, M., Niederhoffer, N., Madrer, N., Yayon, N., Bennett, E. R., Greenberg, D. S., Kadener, S., Soreq, H. NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug‐inducible neuroprotection from oxidative stress. FASEB J. 33, 11223–11234 (2019). http://www.fasebj.org

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

“…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.…”

“…Correspondingly, we identified DANCR as prominently reduced under SARS-CoV-2 infection, together with the lncRNA NEAT1 which controls RNA-regulating processes via forming the non-membranous organelle of the nuclear paraspeckles. Of note, NEAT1 interacts with inflammatory pathways, leading to transcriptional activation of IL-8 ( 110 ) and protecting human-originated neuronal cells under oxidative stress in a manner mediated by lipid lowering medications (such as statins) ( 33 ). NEAT1 is further implicated in inflammation by its association with controllers of inflammasome-associated proteins, and by its assembly with other molecular elements into an immune-controlling ribonuclear complex ( 111 , 112 ).…”

“…It is therefore possible that these small regulatory molecules and their interactions with long non-coding RNAs are part of the COVID-19 pathogenesis. If so, they also provide therapeutic targets and opportunities for intervention, possibly in conjunction with other immunomodulatory efforts ( 165 ) and with agents which may upregulate the expression of NEAT1, such as statins ( 33 ). In conclusion, establishing the interlinks between specific ncRNAs and their targets may augment our understanding of the inflammatory course of COVID-19, aid in designing intervention strategies, and lead to potential novel diagnostic and therapeutic means.…”

“…NcRNAs span short microRNAs (miRs), long non-coding RNA (lncRNAs) longer than 200 nucleotides, and other types of ncRNAs. Under acute or chronic challenges, ncRNAs interact with other ncRNAs, coding messenger RNAs (mRNAs), or directly with proteins, modifying their actions and affecting various clinical conditions including inflammation ( 32 , 33 ). Specifically, several ncRNAs react to chronic, subacute inflammation, such as in the metabolic syndrome and its components and in the organismal response to infections ( 34 , 35 ).…”

Long non-coding NEAT1 weakens the protective role of sevoflurane on myocardial ischemia/reperfusion injury by mediating the microRNA-140/RhoA axis

“…NEAT1 has been most frequently studied in various cancer as an oncogene, including cervical cancer [22], colon cancer [23] as well as glioma [24] by regulating cell migration, proliferation along with drug resistance. Additionally, NEAT1 was upregulated in Parkinson's disease and conferred drug-inducible neuroprotection against oxidative stress [25]. Also, NEAT1 expression was enhanced in patients suffered from acute ischemic stroke versus controls, which could predict unsatisfactory recurrence-free survival [26].…”