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 appears 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 identified a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNA are known 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 neuroblast cells. In contrast MPP+ activates the NLPR3 inflammasome through miR590-3p up-regulation, and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p exposing a novel therapeutic target to prevent excessive inflammasome activation and pyroptosis in neuroblast cells during Parkinson's disease.

LncZFAS1 Inhibit MPP+-Induced Neuroinflammation Through TXNIP/MIB1 E3 Ubiquitin Ligase/NLRP3 Axis

“…Recently, Qin et al reported that MIB1 overexpression relieved apoptosis and inflammation of cardiac microvascular endothelial cells during coronary microvascular dysfunction by targeting the ASK1/p38 pathway [72]. In agreement with the hypothesis, lncZFAS1 overexpression directly interfered with mir590-3p to inhibit TXNIP the MIB1 E3 ubiquitin ligase/NLRP3 pathway [6]. Finally, we consider that LncZFAS1 can be used as an important regulatory target for neuroinflammatory pathways in PD.…”

“…NLRP3 is an inflammatory complex mainly present in microglia and contains a caspase activation recruitment domain and caspase-1, which promotes the secretion of IL-1/ IL-18 and induces pyroptosis to destroy microglia to further release IL-1 [36][37][38]. Our results showed that SH-SY5Y cells generated and activated NLRP3 to induce cellular pyroptosis [6], revealing the role of NLRP3 and cells other than microglia in the neuroinflammatory response in PD. Besides, NLRP3 inflammasome activation may aggravate dopaminergic neuronal loss in Parkinson's disease [39].…”

“…In our study, NLPR3 activation, ASC recruitment, caspase-1 cleavage, and IL-1 release were found to be dependent on TXNIP/TRX1 interaction. Increased TXNIP ubiquitination by MIB1 E3 ubiquitin ligase can regulate NLRP3 inflammasome activation in SH-SY5Y cell [6]. In the above chapter, we mention innate immunity and adaptive immunity.…”

“…Harnessing inflammatory responses through targeted modulation of innate and adaptive immune responses has gained increasing interest in recent years as a potential therapeutic strategy. One of our articles, "A Novel Long-Noncoding RNA LncZFAS1 Prevents MPP + -Induced Neuroinflammation Through MIB1 Activation, " was studied on this topic and published online in Molecular Neurobiology in December, 2021 [6]. We explored the interaction of the LncZFAS1 and miR590-3p/TXNIP/MIB1 E3 ubiquitin ligase/NLRP3 pathway in the inflammation of PD.…”

“…In contrast, MPTP activated NLPR3 inflammasome through miR590-3p upregulation and directly interfered with MIB1-dependent TXNIP ubiquitination. LncZFAS1 overexpression inhibits this entire pathway through direct interference with miR590-3p, suggesting a novel research idea in mechanism of PD [6].…”