Mustafa Sahin

I am investigating the normal cellular functions of signaling pathways implicated in neurological disease, with an emphasis on neuronal connectivity. My research centers upon the proteins affected in tuberous sclerosis complex (TSC), a neurological disorder whose genetic basis is well understood but whose cell biology in the brain remains less well understood. As a clinical neurologist, I also treat patients with TSC and related neurodevelopmental disorders. One of the ultimate goals of our research is to guide the development of therapeutics for disorders of neural connectivity. My team is currently conducting clinical trials investigating new treatments for TSC and related disorders.

Tuberous Sclerosis Complex:

TSC is a multi-system autosomal dominant disease caused by loss-of-function mutations in the TSC1 or TSC2 gene. This disease is characterized by the formation of benign tumors (hamartomas) in several organs. The brain is almost invariably affected, and patients often present with epilepsy, autism and intellectual disability. We hypothesize that a miswiring of neuronal connections may underlie these neurological symptoms.

We discovered that the TSC1 and TSC2 proteins regulate axon formation and growth. In mouse models of TSC, we observe ectopic axons and abnormal axon path-finding in the brain. The axonal functions of the TSC proteins may be important in understanding the neurological features of the disease--and, more generally, in understanding the pathology of the autism spectrum disorders that affect patients both with and without TSC.

We are further exploring the molecular network in which the TSC1/2 proteins function and have found that modulation of the growth-promoting mTOR pathway, which is regulated by TSC proteins, can contribute to other neuronal functions of the TSC signaling network, such as the control of neuron size, myelination, autophagy, mitochondrial dynamics and stress responses. For instance, my lab, in collaboration with others, has shown that in a mouse model of TSC, neurons are sized abnormally, are not sufficiently myelinated and are prone to cell death. In other studies, we have found that TSC activity mediates mTOR's response to neuronal stress. In particular, neurons lacking a functional TSC protein complex are more vulnerable to endoplasmic reticulum stress-induced cell death.

More recently, we have been investigating the role of TSC/mTOR signaling cascade in specific circuits in the CNS. We have generated a cerebellar Purkinje neuron-specific knockout of Tsc1 that displays autistic features, such as impairments in social interaction, repetitive behaviors and ultrasonic vocalizations. Importantly, treating these mice with an mTOR inhibitor prevents the development of these aberrant behaviors. Interestingly, human Purkinje neurons derived from TSC-patient iPSC’s also recapitulate most of the cellular phenotypes we see in our mouse model.

We are now using a combination of iPSC-derived neurons in culture, mouse models and human EEG and imaging to better characterize the neuronal connectivity deficits in TSC and related developmental disorders with the goal of developing new therapies for these children.