Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

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.

Neuroproteomics in Epilepsy: What Do We Know so Far?

“…In summary, through the enrichment gene ontology analysis, the researchers found that DE proteins were mainly the components of synaptic membranes; the biological processes that were highly enriched were amino acid metabolism and the molecular functions related to antioxidant activity, ligase activity, and tetrapyrrole binding, which had an especially high number of DE proteins. Taken together, these data suggest that TSC mutations or alterations in patients’ synaptic proteins may affect the information transmission in the cells, and changes in patients’ amino acid metabolism can be a new mechanism to be explored in the TSC complex context (Liu et al, 2020 ).…”

“…A very recent study (Liu et al, 2020 ) reported mutation analyses, clinical features, and tissue proteomic profiles of three patients with epilepsy caused by truncating TSC1 mutations. The authors used a DIA (Data-independent acquisition) workflow to explore the proteomic profile of these patients compared with control tissue from craniocerebral trauma surgery and found downregulation of ARFGEF2, which has been associated with intellectual disability and abnormal neuronal migration (Hong et al, 2018 ; Liu et al, 2020 ).…”

“…A very recent study (Liu et al, 2020 ) reported mutation analyses, clinical features, and tissue proteomic profiles of three patients with epilepsy caused by truncating TSC1 mutations. The authors used a DIA (Data-independent acquisition) workflow to explore the proteomic profile of these patients compared with control tissue from craniocerebral trauma surgery and found downregulation of ARFGEF2, which has been associated with intellectual disability and abnormal neuronal migration (Hong et al, 2018 ; Liu et al, 2020 ). DCX upregulation may also be involved with intellectual disability, abnormal neuronal localization, epilepsy (des Portes et al, 1998 ; Lee et al, 2003 ; Liu et al, 2020 ), and decreased levels of ATG12, a protein related to autophagy (Wang et al, 2019 ).…”

“…The authors used a DIA (Data-independent acquisition) workflow to explore the proteomic profile of these patients compared with control tissue from craniocerebral trauma surgery and found downregulation of ARFGEF2, which has been associated with intellectual disability and abnormal neuronal migration (Hong et al, 2018 ; Liu et al, 2020 ). DCX upregulation may also be involved with intellectual disability, abnormal neuronal localization, epilepsy (des Portes et al, 1998 ; Lee et al, 2003 ; Liu et al, 2020 ), and decreased levels of ATG12, a protein related to autophagy (Wang et al, 2019 ). Moreover, Liu et al ( 2020 ) identified decreased levels of K + channel proteins (KCNA2 and KCNAB2) in the TSC1 mutation group compared with the controls; these changes have been associated with epilepsy due to the proteins’ role in membrane excitability (Jan and Jan, 1997 ; Liu et al, 2020 ).…”

“…DCX upregulation may also be involved with intellectual disability, abnormal neuronal localization, epilepsy (des Portes et al, 1998 ; Lee et al, 2003 ; Liu et al, 2020 ), and decreased levels of ATG12, a protein related to autophagy (Wang et al, 2019 ). Moreover, Liu et al ( 2020 ) identified decreased levels of K + channel proteins (KCNA2 and KCNAB2) in the TSC1 mutation group compared with the controls; these changes have been associated with epilepsy due to the proteins’ role in membrane excitability (Jan and Jan, 1997 ; Liu et al, 2020 ). In summary, through the enrichment gene ontology analysis, the researchers found that DE proteins were mainly the components of synaptic membranes; the biological processes that were highly enriched were amino acid metabolism and the molecular functions related to antioxidant activity, ligase activity, and tetrapyrrole binding, which had an especially high number of DE proteins.…”