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1.
DNA Cell Biol ; 41(9): 789, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35834551
2.
DNA Cell Biol ; 39(11): 1913, 2020 11.
Article in English | MEDLINE | ID: mdl-33155840
4.
DNA Cell Biol ; 39(1): 2, 2020 01.
Article in English | MEDLINE | ID: mdl-31928431
5.
DNA Cell Biol ; 37(3): 153, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29406770
6.
DNA Cell Biol ; 37(1): 1, 2018 01.
Article in English | MEDLINE | ID: mdl-29211498
9.
DNA Cell Biol ; 35(5): 209, 2016 May.
Article in English | MEDLINE | ID: mdl-27093464
14.
Epilepsia ; 55(4): 539-50, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24512506

ABSTRACT

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.


Subject(s)
Brain Diseases/diagnosis , Brain/abnormalities , Tuberous Sclerosis/diagnosis , Brain/growth & development , Brain Diseases/metabolism , Brain Diseases/pathology , Cerebral Cortex/abnormalities , Cerebral Cortex/growth & development , Cerebral Cortex/pathology , Female , Humans , Male , Prospective Studies , Tuberous Sclerosis/metabolism , Tuberous Sclerosis/pathology
16.
DNA Cell Biol ; 32(9): 487, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23965148
17.
DNA Cell Biol ; 32(7): 341, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23815340
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