Many of the most challenging diseases confronting child neurologists are genetic disorders that disrupt signaling pathways. These abnormal signaling pathways, when present in neurons and glia, can give rise to epilepsy, cognitive disorders, behavior problems, structural brain defects, and other neurodevelopmental problems. Dr. Robert Carson studies abnormal signaling pathways in the brain, with the goals of understanding mechanisms of childhood neurologic disease and developing cures for them. Robert Carson, MD, PhD, an Assistant Professor of Pediatrics and Neurology at Vanderbilt University, currently focuses on a specific genetic disorder – tuberous sclerosis complex (TSC). As all child neurologists know, TSC is inheritable as an autosomal dominant disease whose signs and symptoms typically include epilepsy, cognitive disturbances, attention deficits, and autism. A hamartomatous disorder, TSC is caused by loss of function mutations in either the TSC1 or TSC2 genes that encode hamartin and tuberin, respectively. These proteins function, at least in part, to regulate the mammalian target of rapamycin (mTOR), which is a protein kinase. mTOR exerts its actions within two distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
The ongoing goal is to find therapies which may improve epilepsy and cognition.
Over the course of the past decade, a great deal of research has demonstrated that alteration in mTORC1 signaling can disrupt brain development and function, thus contributing strongly to the symptoms of TSC. In contrast, much less information has been known about the role of mTORC2. Thus, with the goal of better understanding the pathogenesis of TSC, Dr. Carson sought to unveil the role of mTORC2 in brain development and function.
A critical component of mTORC2 is the protein Rictor (rapamycin insensitive component of TOR). Dr. Carson’s strategy for determining the function of mTORC2 was to inactivate Rictor. Thus, Dr. Carson and his colleagues created mice containing a conditional knockout of the Rictor gene in the brain’s dorsal neuroprogenitor cells. He found that the mutant mice have abnormally small cortical neuron size, hypomyelination of cerebral white matter, and altered levels of several monoamine neurotransmitters. Behavioral testing revealed that the mice are hyperactive and have disordered sleep.
Thus, Dr. Carson’s research has revealed a clear role for Rictor in brain development and function. His results suggest that TSC reflects a disruption, not just in the function of mTORC1, but in mTORC2, as well. Dr. Carson’s findings have expanded our knowledge of TSC pathogenesis and have broadened the potential targets through which TSC could be treated. Ongoing studies aim to determine the roles of the Tsc2 and Rictor genes in myelination with the continued goal of finding therapies which may improve epilepsy and cognition.
FIGURE 1: Hypomyelination resulting from loss of the Tsc2 gene in oligodendrocytes. Sudan black and myelin basic protein (MBP) immunofluorescence staining of sagittal brain sections of P17 control (A) and Olig2-CKO (B) brains in which Tsc2 was deleted from oligodendrocytes demonstrates diffuse decreases in myelin and the number of oligodendrocytes precursors (olig2). Ex-vivo imaging of control (C) and CKO (D) mouse brains with a 15.2 T MRI demonstrated decreased fractional anisotropy in white matter tracts consistent with that seen in human TSC patients, suggesting a role of oligodendrocytes and myelin in disease pathology. cc=corpus callosum, ac=anterior commissure. Scale bar=100um. (Carson et al., unpublished data; in collaboration with Mark Does.)
Editor’s Note: If you find signaling pathways arduous, raise your hand. Am I the only one with my hand flailing in the air? I have always been terrible at signaling pathways. I can’t remember them, and I don’t like them. When I am shown words like “Erk”, “STAT”, and “Wnt” connected together with arrows, all I see is spaghetti. However, while I realize that I have a personal blind spot for signaling pathways, I fully appreciate their importance. A lot of pediatric neurological diseases (most of them, probably) are ultimately due, in one way or another, to abnormal signaling pathways. Our field is lucky to have people like Dr. Robert Carson, who has the patience and skills to sort out these pathways. You can put your hands down now.