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Revisiting Brain Tuberous Sclerosis Complex in Rat and Human: Shared Molecular and Cellular Pathology Leads to
Viera Kútna1, Valerie B O'Leary2, Ehren Newman3
1Department of Experimental Neurobiology, National Institute of Mental Health, Topolová 748, 250 67, Klecany, Czech Republic. viera.kutna@nudz.cz.
Abstract:
Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans.
Insights
Tuberous sclerosis complex (TSC) is a genetic disorder causing brain tumors. This study compares human and rat TSC brain pathology, revealing shared mechanisms but distinct manifestations that need further research.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder.
- It results from loss-of-function mutations in TSC1 or TSC2 genes.
- This leads to uncontrolled mammalian target of rapamycin C1 (mTORC1) pathway activation, driving cell growth and tumor formation, particularly in the brain.
Purpose of the Study:
- To compare the histopathological, electrophysiological, and neurobehavioral characteristics of brain TSC in humans and Eker rats.
- To identify shared and distinct aspects of the disease pathology between species.
- To explore factors contributing to observed phenotypic discrepancies.
Main Methods:
- Comparative analysis of human and Eker rat brain tissue.
- Histopathological examination of lesions.
- Electrophysiological recordings to assess neuronal activity.
- Neurobehavioral testing to evaluate functional deficits.
Main Results:
- Both humans and Eker rats exhibit similar molecular pathology of TSC due to shared genetic mutations.
- However, significant differences were observed in lesion distribution, developmental profiles, and neurophysiological and behavioral manifestations.
- These discrepancies highlight complexities in TSC's presentation across species.
Conclusions:
- Despite a common genetic and molecular basis, the phenotypic presentation of TSC in the Eker rat model deviates from human disease.
- These differences suggest an incomplete understanding of TSC pathogenesis and disease variability.
- Further research is needed to refine the TSC rat model and better explain clinical variability in human patients.
