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

• Published in: Molecular neurobiology Vol. 59; no. 2; pp. 778 - 799
• Main Authors: Zhu, Ziman, Huang, Peiling, Sun, Ruifeng, Li, Xiaoling, Li, Wenshan, Gong, Weijun
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2022; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Biology; Humans; IL-1β; Inflammasomes; Inflammasomes - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; Mitochondria; Movement disorders; MPP; Neurobiology; Neuroblasts; Neurodegenerative diseases; Neuroinflammatory Diseases; Neurology; Neurosciences; Next-generation sequencing; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Non-coding RNA; Parkinson's disease; Proteasomes; Pyroptosis; RNA, Long Noncoding - metabolism; Synuclein; Transcription; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; TXNIP; NLRP3; Pyroptosis; LncZFAS; Parkinson’s disease; MIB1
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02619-z

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.