A Novel Long-Noncoding RNA LncZFAS1 Prevents MPP+-Induced Neuroinflammation Through MIB1 Activation

Abstract

Parkinson’s disease remains one of the leading neurodegenerative diseases in developed countries. Despite well-defined symptomology and pathology, the complexity of Parkinson’s disease prevents a full understanding of its etiological mechanism. Mechanistically, α-synuclein misfolding and aggregation appear to be central for disease progression, but mitochondrial dysfunction, dysfunctional protein clearance and ubiquitin/proteasome systems, and neuroinflammation have also been associated with Parkinson’s disease. Particularly, neuroinflammation, which was initially thought to be a side effect of Parkinson’s disease pathogenesis, has now been recognized as driver of Parkinson’s disease exacerbation. Next-generation sequencing has been used to identify a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNAs are known to be regulators of inflammatory signaling and neurodegenerative diseases, including IL-1β secretion and Parkinson’s disease. Here, LncZFAS1 was identified as a regulator of inflammasome activation, and pyroptosis in human neuroblast SH-SY5Y cells following MPP+ treatment, a common in vitro Parkinson’s disease cell model. Mechanistically, TXNIP ubiquitination through MIB1 E3 ubiquitin ligase regulates NLRP3 inflammasome activation in neuroblasts. In contrast, MPP+ activates the NLPR3 inflammasome through miR590-3p upregulation and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p, exposing a novel research idea regarding the mechanism of Parkinson’s disease.

rTMS improves dysphagia by inhibiting NLRP3 inflammasome activation and caspase-1 dependent pyroptosis in PD mice

“…Damaged dopaminergic neurons can further activate NLRP3 in ammasome and pyroptosis, forming a vicious cycle [31] . TXNIP, as an upstream molecule of NLRP3 in ammasome, is positively correlated with NLRP3 [32] .Under disease or stress conditions, the levels of reactive oxygen species (ROS) in cells increase, leading to the separation of TXNIP from Trx1, thereby activating TXNIP. The activated TXNIP binds to NLRP3 protein, triggering the self-assembly of NLRP3, ASC and caspase 1, thereby forming the NLRP3 in ammasome complex [33] .The team used SH-SY5Y cell line to establish PD model in vitro, and found that LncRNA ZFAS1 was highly expressed in MPTP-induced PD cell model.…”

LncRNA ZFAS1 Alleviated NLRP3 Inflammasome-Mediated Pyroptosis through Regulating miR-96-5p/Smad7 Signaling in Allergic Rhinitis

“…With respect to pyroptosis, a study identified ZFAS1 as one of eight pyroptosis-related prognostic lncRNAs for oral squamous cell carcinoma using clinicopatholog-ical data, revealing its potential as part of a signature for patient risk stratification and predicting clinical outcomes including overall survival and tumor immune microenvironment [25]. Zhu et al [26] proved that ZFAS1 was a regulator of inflammasome activation and pyroptosis in human neuroblast SH-SY5Y cells following 1-methyl-4-phenylpyridinium (MPP + ) treatment that related with Parkinson's disease. Consistently, in the present study, we found that ZFAS1 was downregulated in allergic rhinitis, and overexpression of ZFAS1 significantly promoted cell viability and inhibited pyroptosis.…”

The roles of ubiquitination and deubiquitination of NLRP3 inflammasome in inflammation-related diseases: A review

“…This altered expression inhibited mindbomb E3 Ub protein ligase 1 (MIB1) protein expression and directly interfered with the MIB1-dependent ubiquitination of thioredoxin interacting protein (TXNIP). As a result, NLPR3 inflammasomes were activated, promoting inflammatory response and pyroptosis in SH-SY5Y cells [ 65 ]. A loss of Parkin activity and overaccumulation of NLRP3 inflammasome was observed in the brain tissues of LPS-induced mouse models of Parkinson’s disease (PD).…”