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.
Highlights
Parkinson’s disease is one of the leading neurodegenerative diseases in developed countries, affecting 1–2% of the elderly population[1]
To determine whether MPP+ can induce inflammasome activation and pyroptosis in human neuroblast cells, SH-SY5Y cells were treated with MPP+ in increasing concentrations, and the frequency of pyroptotic cells was quantified by propidium iodide (PI) internalization and caspase-1 activation
Exploration of the non-coding genome unveiled a panoply of formerly unknown long noncoding RNAs (lncRNA) with critical regulatory functions in the pathophysiology of many neurological diseases[42,43,44,45,46,47,48]
Summary
Parkinson’s disease is one of the leading neurodegenerative diseases in developed countries, affecting 1–2% of the elderly population (above 65 years old)[1]. The World Health Organization predicts that the incidence of Parkinson’s disease will double by 2030[2], resulting in a significant loss of healthy life years. Parkinson’s disease syndrome is defined by tremor, rigidity, progressive akinesia, and/or. Without a well-defined etiological model, the development and identification of novel therapeutic targets must rely on high throughput screening in immortalized or primary neural cell lines[4]. SH-SY5Y human neuroblasts are commonly used as an alternative to laborious and highly heterogeneous primary dopaminergic neuron cultures from rat/mouse embryos[5, 6]. Regardless of the cell model, 1-methyl-4-phenylpyridinium (MPP+) is used to induce Parkinson’s disease-like cellular disease. Regardless of the cell model, 1-methyl-4-phenylpyridinium (MPP+) is used to induce Parkinson’s disease-like cellular disease. MPP+ is a
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