Neuroinflammation, TNF, and Ceramide Signaling: Putative Pathways for Neurotoxicity in Parkinson's Disease

Parkinson’s disease is a progressive neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra that innervate the striatum, and it is the loss of these neurons that causes the motor dysfunction that is associated with the disease. However, the mechanisms that contribute to the induction and perpetuation of dopaminergic neuronal cell death in Parkinson’s disease are multifaceted and poorly understood. Inflammation has been shown to contribute to cytotoxicity in animal models of Parkinson’s disease, and increased levels of inflammatory cytokines have been observed in the cerebral spinal fluid and striatum of Parkinson’s disease patients. We have previously demonstrated that blocking soluble tumor necrosis factor (TNF) signaling with dominant-negative TNF inhibitors attenuates the loss of dopaminergic neurons in models of Parkinson’s disease, but which signaling pathways downstream of TNF mediate this effect remain undetermined. Here, I show that TNF-dependent ceramide signaling contributes to dopamine neuron cytotoxicity by compromising mitochondrial membrane potential, inducing endoplasmic reticulum stress and activating caspase signaling in vitro. My data demonstrate that TNF-induced cytotoxicity is partially ceramide-dependent, as TNF-induced cytotoxic effects are attenuated with two different pharmacological inhibitors of sphingomyelinase, an enzyme that hydrolyzes active ceramide from inactive sphingomyelin pools. Collectively, my data support a model whereby low-dose TNF and concomitant low TNF receptor1 occupancy activates downstream ceramide signaling and metabolism, culminating in caspasedependent cytotoxic cell death of dopaminergic neurons. My data and the data associating ceramide biology and metabolism with Parkinson’s disease warrants future studies examining the potential neuroprotective effects of inhibition of sphingomyelinase in animal models of Parkinson’s disease, and may eventually lead to improved therapy for patients who suffer from Parkinson’s disease.