Studying Protein Synthesis-Dependent Synaptic Changes in Tuberous Sclerosis

Principal Investigator: YOSHII, AKIRA
Institution Receiving Award: ILLINOIS, UNIVERSITY OF, AT CHICAGO
Program: TSCRP
Proposal Number: TS080074
Award Number: W81XWH-09-1-0088
Funding Mechanism: Career Transition Award
Partnering Awards:
Award Amount: $567,840.00


Tuberous sclerosis complex (TSC) is a genetic disorder that involves multiple organs including the brain, kidney, and heart. Neurological symptoms of TSC include seizures, autistic behavior, and mental retardation. TSC is caused by mutations in two genes, TSC1 (Hamartin) and TSC2 (Tuberin), both of which play important roles in protein synthesis and cell growth. Since TSC proteins are negative regulators of mTOR, an enhancer for protein synthesis, mutations causing hypofunction of TSC1 or TSC2 can theoretically induce abnormally increased production of proteins. However, it is unknown which neuronal proteins mTOR regulates and how malfunction in the TSC/mTOR pathway results in the neurological symptoms of TSC.

Patients with TSC have masses called tubers in their brains. While a tuber often becomes a focus of seizures, it does not explain all aspects of TSC's neurological features. I propose to study whether it is neurons themselves that are malfunctioning in TSC. Neurons communicate to each other at a junction called a synapse. At a synapse, one neuron releases neurotransmitter and a neighboring neuron receives the signal through its receptors. There are two kinds of synapses, excitatory and inhibitory. The former typically uses glutamate as a neurotransmitter while the latter uses GABA. Normally, they exist in a dynamic equilibrium, but excitation overwhelms neural circuitry in seizures. This type of imbalance is also thought to account for autistic behavior.

To examine if seizures and other neurological symptoms of TSC are rooted in dysregulated excitatory and inhibitory receptor expression, I will compare the amounts of surface receptors between TSC and normal neurons. Rapamycin, an mTOR inhibitor, has recently been reported to be beneficial for seizure control and overall health in TSC mutant mice. Thus, I will also examine whether rapamycin will affect surface expression of excitatory and inhibitory receptors. The results of these experiments will help determine whether the balance of excitation and inhibition is affected in TSC. They will also determine whether the proposed effect of rapamycin on seizure control is by way of correcting imbalance between excitation and inhibition.

Levels of surface receptors correlate with learning and memory. Memory storage has two phases: short-term and long-lasting. Protein synthesis is required for long-lasting memory, and impaired long-lasting memory results in mental retardation, which is often seen in TSC. Therefore, the next important question is if and how the synaptic dysfunction in TSC is caused by abnormal protein synthesis. Thus, I aim to identify overproduced neuronal proteins in TSC, and then characterize their functions. The results of these experiments will likely advance our understanding of neurobiological basis of TSC and hopefully facilitate the identification of a therapeutic target for neurological symptoms of this challenging disorder.