Impaired myelin production due to an intrinsic failure of oligodendrocytes in mTORpathies

Abstract

Aims We aim to evaluate if the myelin pathology observed in epilepsy‐associated focal cortical dysplasia type 2B (FCD2B) and—histologically indistinguishable—cortical tubers of tuberous sclerosis complex (TSC) is primarily related to the underlying malformation or constitutes a secondary phenomenon due to the toxic microenvironment created by epileptic seizures. We also aim to investigate the possible beneficial effect of the mTOR pathway regulator everolimus on white matter pathology. Methods Primary mixed glial cell cultures derived from epilepsy surgery specimens of one TSC and seven FCD2B patients were grown on polycaprolactone fibre matrices and analysed using immunofluorescence and electron microscopy. Unaffected white matter from three age‐matched epilepsy patients with mild malformations of cortical development (mMCD) and one with FCD3D served as controls. Additionally, TSC2 knock‐out was performed using an oligodendroglial cell line. Myelination capacities of nanofibre grown cells in an inflammatory environment after mTOR‐inhibitor treatment with everolimus were further investigated. Results Reduced oligodendroglial turnover, directly related to a lower myelin content was found in the patients' primary cells. In our culture model of myelination dynamics, primary cells grown under ‘inflammatory condition’ showed decreased myelination, that was repaired by treatment with everolimus. Conclusions Results obtained in patient‐derived primary oligodendroglial and TSC2 knock‐out cells suggest that maturation of oligodendroglia and production of a proper myelin sheath seem to be impaired as a result of mTOR pathway disturbance. Hence, oligodendroglial pathology may reflect a more direct effect of the abnormal genetic programme rather than to be an inactive bystander of chronic epilepsy.

Identification of gene regulatory networks affected across drug-resistant epilepsies

“…The mTORopathies presented a speci c activated regulome associated with neuronal support and myelination. Multiple studies have shown a link between hyperactivation of mTOR pathway and myelin de ciency, impairment of proliferation and differentiation of oligodendrocytes progenitor cells as well as oligodendroglial turnover 22,23 . Our transcriptomic data corroborate for the rst time the reported literature ndings.…”

Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders

“…In a human study, primary mixed glial cell cultures derived from patients with TSC or focal cortical dysplasia, which is a histologically close condition, reduced oligodendroglial turnover in association with a lower myelin content. In addition, mTOR inhibitors repair decreased myelination ( 92 ). Two studies have reported that mTOR inhibitors change the white matter microstructure ( 88 , 89 ).…”

GABAA receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β

“…The immunofluorescent labelling was performed as previously described 66 by incubating NeuN (mouse monoclonal, clone MAB377; Chemicon, Temecula, CA, USA; 1:2.000), microtubule-associated protein (MAP2; mouse clone HM2; Sigma 1:100) and glial fibrillary acidic protein (GFAP; mouse monoclonal, clone GA5, Sigma-Aldrich, St. Louis, MO, USA; 1:4.000) antibody with the primary antibody against IL-10Rα. Sections were analyzed using Leica Confocal Microscope TCS SP8 X DLS (Leica, Son, the Netherlands) at 20 × magnification (bidirectional X, speed 600 Hz, pinhole 1.00 AU).…”