Understanding the role of alpha-synuclein in Japanese encephalitis virus replication and evaluation of pyrazole derivatives as therapeutics against its infection

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In the prognosis of Japanese encephalitis virus (JEV) infection, many host factors have been identified as being involved in the various steps of the viral life cycle. Since it is a neurotropic virus, understanding the role of neuronal-specific proteins and local cellular homeostasis in developing therapeutics against JEV is an active area of research. Alpha-synuclein (α-syn) is one of the neuronal-specific proteins regulating synaptic plasticity and has been reported to have antiviral potential in related neurotropic viruses. JEV-infected patients displaying Parkinson's disease (PD)-like symptoms have been reported to have α-syn overexpression in the brain regions. As per reports, phosphorylation at S129 position plays a major role in aggregation and α-synucleinopathy. Therefore, exploring the function of α-syn in JEV induced death of dopaminergic neurons and α-synucleinopathy is essential. To this day, the present study reports the functional role of α-syn in JEV pathogenesis as well as explores the anti-JEV therapeutic candidates. There is a significant increase in endogenous α-syn expression during JEV replication, demonstrating a substantial reduction in JEV replication, suggesting an anti-JEV effect. α-syn was found to modulate the anti-oxidative pathway by increasing the expression of superoxide dismutase 1 (SOD1). The pathological implications of α-syn phosphorylation were carried out by studying casein kinase 2 (CK2) and Polo-like kinase (PLK2) involved in α-syn phosphorylation. Detailed analyses of CK2 and PLK2 reveal a notable reduction in these kinases, particularly during the late phase of JEV replication, thereby reducing the phosphorylated α-syn (pα-synS129) protein level. The intracellular α-syn oligomerization was increased in JEV-infected cells. Pyrazole derivatives with anti-oxidative properties were found to have anti-JEV activity. Comprehensive in vitro and in vivo studies showed compounds suppressed JEV-induced reactive oxygen species (ROS) generation through NRF2-SQSTM1 signaling mechanisms. This study contributes valuable insights into the interplay between α-syn and JEV, shedding light on avenues to study further the potential role of α-syn aggregation in JEV pathogenesis and exploit it to develop broad-spectrum antiviral therapeutics.
Supervisors: Kumar, Sachin and Chaudhary, Nitin