Aberrant expression of long noncoding RNAs regulates inflammasome activation via oxidative stress: A novel mechanism for neuroinflammation and neurodegeneration in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to hallmark motor symptoms such as bradykinesia, tremors, and rigidity. Emerging evidence suggests that the dysregulation or aberrant expression of long noncoding RNAs (lncRNAs) plays a critical role in the pathogenesis of PD by activating the inflammasome, either directly or via oxidative stress. Aberrant lncRNA expression has been linked to alterations in genes related to oxidative stress, causing an imbalance between reactive oxygen species (ROS) and antioxidant defenses. This imbalance contributes to mitochondrial dysfunction and neuronal damage. The NLRP3 inflammasome is a multiprotein complex comprising a sensor protein (eg, NLRP3), an adaptor protein (ASC), and an effector protein (caspase-1). Its activation involves priming via NF-κB signaling and is triggered by ROS, mitochondrial dysfunction, death-associated molecular patterns, or extracellular ATP. Once activated, the inflammasome promotes the cleavage and maturation of the proinflammatory cytokines IL-1β and IL-18, amplifying neuroinflammation and leading to neurodegeneration in PD. Crosstalk between dysregulated lncRNAs, ROS production, and inflammasome activation creates a vicious cycle of neuroinflammation and neurodegeneration, exacerbating PD progression. This review explores the molecular mechanisms linking lncRNA dysregulation to inflammasome activation in PD, either directly or through oxidative stress. It also highlights key lncRNAs involved in these processes. Furthermore, potential therapeutic strategies targeting these pathways, such as antioxidants, lncRNA modulators, and inflammasome inhibitors, offer promising avenues to mitigate neuroinflammation and slow neurodegeneration in PD.