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Emerging Role of Long Noncoding RNAs in Regulating Inflammasome-Mediated Neurodegeneration in Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is one of the complex neurodegenerative disorders, primarily characterized by motor deficits, including bradykinesia, tremor, rigidity, and postural instability. The underlying pathophysiology involves the progressive loss of dopaminergic neurons within the substantia nigra pars compacta, leading to dopamine depletion in the basal ganglia circuitry. While motor symptoms are hallmark features of PD, emerging research highlights a wide range of non-motor symptoms, including cognitive impairments, mood disturbances, and autonomic dysfunctions. Inflammasome activation is pivotal in inducing neuroinflammation and promoting disease onset, progression, and severity of PD. Several studies have shown that long noncoding RNAs (lncRNAs) modulate inflammasomes in the pathogenesis of neurodegenerative diseases. Dysregulation of lncRNAs is linked to aberrant gene expression and cellular processes in neurodegeneration, causing the activation of inflammasomes that contribute to neuroinflammation and neurodegeneration. Inflammasomes are cytosolic proteins that form complexes upon activation, inducing inflammation and neuronal cell death. This review explores the significance of lncRNAs in regulating inflammasomes in PD, primarily focusing on specific lncRNAs such as nuclear paraspeckle assembly transcript 1 (NEATNEAT1), X-inactive specific transcript (XIST), growth arrest-specific 5 (GAS5), and HOX transcript antisense RNA (HOTAIR), which have been shown to activate or inhibit the NLRP3 inflammasome and induce the release of proinflammatory cytokines. Moreover, some lncRNAs mediate inflammasome activation through miRNA interactions. Understanding the roles of lncRNAs in inflammasome regulation provides new therapeutic targets for controlling neuroinflammation and reducing the progression of neurodegeneration. Identifying lncRNA-mediated regulatory pathways paves the way for novel therapies in the battle against these devastating neurodegenerative disorders.

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Abbreviations

AIM2:

Absent in melanoma 2

AKI:

Acute kidney injury

ANRIL:

Antisense noncoding RNA in the INK4 locus

ASC:

Apoptosis-associated speck-like protein containing a CARD

CCI:

Chronic constriction injury

COPD:

Chronic obstructive pulmonary disease

CRNDE:

Colorectal neoplasia differentially expressed

DAMPs:

Danger-associated molecular patterns

DLX6-AS1:

Distal-less homeobox 6 antisense 1

FIRRE:

Functional intergenic repeating RNA element

GAS5:

Growth arrest-specific 5

GBA:

Glucocerebrosidase

GSDMD:

Gasdermin D

HAGLR:

HOXD antisense growth-associated long noncoding RNA

HOTAIR:

LncRNA HOX antisense intergenic RNA

HOTTIP:

HOXA transcript at the distal tip

HOXA11-AS:

Homeobox A11 antisense

HUVEC:

Human umbilical vein endothelial cell

Lfar1:

Liver-fibrosis associated lncRNA1

LRRK2:

Leucine-rich repeat kinase 2

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

MDRL:

Mitochondrial dynamic-related lncRNA

Meg3:

Maternally expressed gene 3

MIAT:

Myocardial infarction-associated transcript

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NACHT:

Nucleotide-binding oligomerization domain

NEAT1:

Nuclear paraspeckle assembly transcript 1

NF-κB:

Nuclear factor-κB

NLRC4:

NOD-like receptor family-C

NLRP1:

NLR family pyrin domain containing 1

NLRs:

Nod-like receptors

NSCLC:

Non-small cell lung cancer

PAMPs:

Pattern-associated molecular patterns

PD:

Parkinson’s disease

Platr4:

Pluripotency-associated transcript 4

PVT1:

Plasmacytoma variant translocation 1

RGMB-AS1:

Repulsive guidance molecule bone morphogenetic protein coreceptor b antisense RNA 1

RMRP:

RNA component of mitochondrial RNAase P

SNHG:

Small nucleolar RNA host gene

TLR:

Toll-like receptors

UC:

Ulcerative colitis

VA-HF:

Ventricular arrhythmia associated with heart failure

XIST:

X-inactive specific transcript

ZFAS1:

Zinc finger antisense 1

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Funding

The study was financially supported by the Science & Engineering Research Board and the Council of Scientific and Industrial Research, Govt. of India, and the Council of Scientific and Industrial Research, Govt. of India, for a Junior Research Fellowship. CL acknowledges the Science & Engineering Research Board, Govt. of India, for Extra Mural Research Grant [EMR/2017/002793], the Indian Council of Medical Research, Govt. of India, for Extra Mural Research Grant [File Number 36/14/2020/TOX/BMS], and UGC for Startup Research Grant. This study is supported via funding from Prince Sattam bin Abdulaziz University project number (PSAU/2023/R/1444).

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Authors and Affiliations

  1. Molecular Pharmacology & Toxicology Laboratory, Department of Biotechnology, School of Life Sciences, Central University of Tamil Nadu, Neelakudi Campus, Thiruvarur, 610005, India

    Narmadhaa Sivagurunathan & Latchoumycandane Calivarathan

  2. Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Kingdom of Saudi Arabia

    Mohamudha Parveen Rahamathulla

  3. University Hospital, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Kingdom of Saudi Arabia

    Hussein Al-Dossary

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  1. Narmadhaa Sivagurunathan
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  2. Mohamudha Parveen Rahamathulla
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  3. Hussein Al-Dossary
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  4. Latchoumycandane Calivarathan
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NS, MPR, HA, and LC developed the concept, designed, and supported in collecting references and writing the manuscript.

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Correspondence to Latchoumycandane Calivarathan.

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Highlights

• Unraveling the role of lncRNAs in the pathogenesis of Parkinson’s disease

• Significance of inflammasome activation by lncRNAs in Parkinson’s disease.

• Understanding the mechanism of lncRNAs in regulating inflammasome-mediated neuroinflammation in Parkinson’s disease.

• A novel insight on lncRNAs for targeted therapies for Parkinson’s disease.

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Sivagurunathan, N., Rahamathulla, M.P., Al-Dossary, H. et al. Emerging Role of Long Noncoding RNAs in Regulating Inflammasome-Mediated Neurodegeneration in Parkinson’s Disease. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03809-7

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