My lab is investigating the normal cellular functions of signaling pathways implicated in neurological disease, with an emphasis on axon growth and guidance. Our research centers upon the proteins affected in tuberous sclerosis complex (TSC) and spinal muscular atrophy (SMA) -- two neurological disorders whose genetic basis is well understood but whose cell biology remains unknown. As a clinical neurologist, I also treat patients with neurological disease. 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.
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 mental retardation. We hypothesize that a miswiring of neuronal connections may underlie these neurological symptoms.
We have recently found that the Tsc1 and Tsc2 proteins restrict 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.
Click to see how TSC proteins control axon development.
We are further exploring the molecular network in which the Tsc proteins function, and have found that modulation of the growth-promoting mTOR pathway, which is regulated by Tsc proteins, can promote axon regeneration in the adult central nervous system. We are also interested in other neuronal functions of the Tsc signaling network, such as the control of neuron size, myelination, survival 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.
Click to see a schematic of the mTOR signaling pathway.
Spinal muscular atrophy
Our second major line of research aims to understand axonal pathology in SMA, an autosomal recessive neuromuscular disease. SMA is characterized by hypotonia and muscle weakness, as spinal motor neurons are lost, and is caused by mutations in the SMN gene.
It is known that the SMN protein controls RNA processing and is important for axon development, but the details remain enigmatic. We hypothesize that axonal RNA transport and/or translation are not properly regulated in the disease. To investigate this, we are characterizing the role of the SMN protein in axon growth and guidance in vivo, as well as identifying proteins and mRNA targets that interact with SMN in neurons. We hope that our work will provide new insight into the signaling mechanisms responsible for establishing brain circuitry, and ultimately suggest therapeutic interventions for disorders in which these signaling mechanisms are perturbed.
About Dr. Sahin
Mustafa Sahin received his MD and PhD in neurobiology at the Yale University School of Medicine. He completed an internship at Children's Hospital of Philadelphia and residencies at both Children's Hospital of Philadelphia and Boston Children's Hospital. He has received numerous awards, including a Mentored Clinical Scientist Development Award, a William Randolph Hearst Fund Award, a Spinal Muscular Atrophy Foundation Young Investigator Award, the 2005 Young Investigator Award from the Child Neurology Society and a 2009 John Merck Scholar Award.