Mechanism-based treatment in tuberous sclerosis complex

Abstract

Background: Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches.

Methods: We performed a literature review to identify ongoing therapeutic challenges and novel strategies.

Results: To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors.

Conclusions: Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach.

Keywords: mTOR; neuronal connectivity; rapamycin; tuberous sclerosis complex.

Figure 1

Schematic of the TSC/mTOR pathway. mTORC1 is activated by growth factors, hormones and nutrients, and regulates cell size and translation via its substrates S6K1 and 4E-BP1. The heterodimeric TSC1/TSC2 complex is activated through AMPK by low energy states and functions via Rheb to inhibit mTORC1 activity. The compound rapamycin inhibits mTORC1 activity downstream of the TSC1/2 complex.

Figure 2

Proposed model of TSC pathomechanism in the brain. Mutation of either TSC1 or TSC2 disrupts the inhibitory function of the TSC1/2 complex. This leads to constitutively increased mTORC1 activity, which in turn results in abnormal neuronal connectivity, characterized by abnormal neuronal morphology and migration, abnormal white matter and impaired synapse function.