ABSTRACT
Temporal lobe epilepsy (TLE) is a severe chronic neurological disease caused by abnormal discharge of neurons in the brain and seriously affect the long-term life quality of patients. Currently, new insights into the pathogenesis of TLE are urgently needed to provide more personalized and effective therapeutic strategies. Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate receptor 2 (S1PR2) signaling pathway plays a pivotal role in central nervous system (CNS) diseases. However, the precise altered expression of SphK1 and S1PR2 in TLE is remaining obscure. Here, we have confirmed the expression of SphK1 and S1PR2 in the pilocarpine-induced epileptic rat hippocampus and report for the first time the expression of SphK1 and S1PR2 in the temporal cortex of TLE patients. We found an increased expression of SphK1 in the brain from both epileptic rats and TLE patients. Conversely, S1PR2 expression level was markedly decreased. We further investigated the localization of SphK1 and S1PR2 in epileptic brains. Our study showed that both SphK1 and S1PR2 co-localized with activated astrocytes and neurons. Surprisingly, we observed different subcellular localization of SphK1 and S1PR2 in epileptic brain specimens. Taken together, our study suggests that the alteration of the SphK1/S1PR2 signaling axis is closely associated with the course of TLE and provides a new target for the treatment of TLE.
ABSTRACT
Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up- and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.
