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Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and
Véronique Ruppe1, Pelin Dilsiz, Carol Shoshkes Reiss
1Department of Neurology, School of Medicine, New York University, New York, New York, U.S.A.
Objective:
Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism.
Methods:
Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens.
Results:
Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination.
Significance:
Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Insights
Tuberous Sclerosis Complex (TSC) brain tissue shows abnormal mTOR signaling and connectivity extending into the perituberal cortex. This suggests the "normal-appearing" tissue contributes to neurological issues in TSC.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by abnormal cell growth.
- Loss of Tsc1/Tsc2 function in TSC leads to dysregulated mammalian target of rapamycin (mTOR) signaling and aberrant brain development.
- Previous research primarily focused on cortical tubers, neglecting the surrounding perituberal cortex.
Purpose of the Study:
- To investigate the cellular and molecular characteristics of the perituberal cortex in TSC.
- To understand the contribution of perituberal cortex to epileptogenesis, cognitive dysfunction, and autism in TSC.
- To compare TSC-related changes in tubers and perituberal cortex with non-TSC epilepsy specimens.
Main Methods:
- Histologic and immunohistochemical analyses of surgically resected cortical tubers and perituberal cortex.
- Western blotting to quantify mTORC1 and mTORC2 pathway biomarkers (phospho-S6, phospho-Akt).
- Evaluation of neuronal and glial-specific protein expression in TSC and non-TSC epilepsy tissues.
Main Results:
- Cortical tubers exhibited disrupted lamination, dysplastic neurons, increased mTORC1, decreased mTORC2 activity, enhanced axonal growth, and hypomyelination.
- Perituberal cortex showed similar but milder histologic and molecular abnormalities compared to tubers.
- Increased axonal growth in TSC was linked to deficient myelination.
Conclusions:
- Cellular dysplasia and mTOR signaling dysregulation extend into the perituberal cortex in TSC.
- Aberrant brain connectivity was identified in human TSC tissue.
- Findings suggest the perituberal cortex is intrinsically epileptogenic and contributes to TSC-related neurological dysfunction.
