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Tweak and TNF family members are novel regulators of acute and chronic inflammation. Tweak / Fn14 interaction appears to be involved in angiogenesis, inflammation, proliferation, migration, cytokine production, cytotoxicity and apoptosis. Thus, TWEAK can induce both cell death and proliferation. Recently, TWEAK has been shown to be associated with neurodegenerative effects in an MPTP mouse model of PD. Despite numerous studies demonstrating TWEAK’s ability to cause cell death in diverse cell types the mechanism(s) by which TWEAK-induce dopaminergic cell death remain poorly defined. Therefore in an attempt to better understand the molecular basis of TWEAK-induced dopaminergic neurotoxicity we evaluated the apoptotic effect of TWEAK and associated molecular mechanisms using N27 dopaminergic neuronal cells. TWEAK-induced a time dependent increase in ROS generation, mitochondrial dysfunction, caspase activation, and NF-kB activation. Additionally, a concurrent activation of SYK and proteolytic cleavage of PKC delta was evidenced in TWEAK treated cells. In contrast a marked down regulation of p-GSK 3b (Ser 9) and Akt activity was evidenced in TWEAK treated cells. Intriguingly, inhibition of SYK activity via R708 attenuated TWEAKinduced loss of dopaminergic cell viability. Likewise, SN50, NF-kB inhibitor and Quercetin, a ubiquitous bioactive plant flavonoid attenuated TWEAK-induced apoptotic cell death further highlighting the pivotal role of NF-kB and mitochondria dependent oxidative stress signaling events in the mechanism of dopaminergic neurodegeneration. Taken together, our studies demonstrate the involvement SYK/NF-kB signaling axis and mitochondrial dysfunction in TWEAK-induced apoptotic cell death. In the next series of studies we determined the effects of TWEAK on microglia. A growing body of evidence suggests that persistent microglial activation and accompanying oxidative stress may act as co-conspirators in mediating dopaminergic

Role of spleen tyrosine kinase in tumor necrosis factor like weak inhibitor of apoptosis induced dopaminergic neuronal cell death and microglial activation in invitro and in vivo models of Parkinson disease