A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesion...
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Elsevier
2018-01-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117302231 |
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| author | Shruti Bagla Daniela Cukovic Eishi Asano Sandeep Sood Aimee Luat Harry T. Chugani Diane C. Chugani Alan A. Dombkowski |
| author_facet | Shruti Bagla Daniela Cukovic Eishi Asano Sandeep Sood Aimee Luat Harry T. Chugani Diane C. Chugani Alan A. Dombkowski |
| author_sort | Shruti Bagla |
| collection | DOAJ |
| description | Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[11C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC. |
| first_indexed | 2024-12-19T10:16:18Z |
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| id | doaj.art-94db65309d3c464e81b9a9b243d13543 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T10:16:18Z |
| publishDate | 2018-01-01 |
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| spelling | doaj.art-94db65309d3c464e81b9a9b243d135432022-12-21T20:26:13ZengElsevierNeurobiology of Disease1095-953X2018-01-011097687A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complexShruti Bagla0Daniela Cukovic1Eishi Asano2Sandeep Sood3Aimee Luat4Harry T. Chugani5Diane C. Chugani6Alan A. Dombkowski7Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USADepartment of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USADepartment of Neurology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USAResearch Department, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Communication Sciences and Disorders Department, College of Health Sciences, University of Delaware, Newark, DE, USADepartment of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Corresponding author at: Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Room 3L22, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201, USA.Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[11C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.http://www.sciencedirect.com/science/article/pii/S0969996117302231Tuberous sclerosis complexEpilepsySeizuremicroRNATryptophanα[11C]-methyl-L-tryptophan |
| spellingShingle | Shruti Bagla Daniela Cukovic Eishi Asano Sandeep Sood Aimee Luat Harry T. Chugani Diane C. Chugani Alan A. Dombkowski A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex Neurobiology of Disease Tuberous sclerosis complex Epilepsy Seizure microRNA Tryptophan α[11C]-methyl-L-tryptophan |
| title | A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| title_full | A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| title_fullStr | A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| title_full_unstemmed | A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| title_short | A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| title_sort | distinct microrna expression profile is associated with α 11c methyl l tryptophan amt pet uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex |
| topic | Tuberous sclerosis complex Epilepsy Seizure microRNA Tryptophan α[11C]-methyl-L-tryptophan |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117302231 |
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