Grant: Project Grant

Leukodystrophies are a group of rare genetic neurological diseases affecting previously healthy children, who become progressively disabled over months to years, eventually succumbing to early death. No curative treatment is available for most of these children. These diseases are characterized by defects in the brain's white matter, whose main component, myelin, is critical for ensuring that brain cells (neurons) are both protected and able to transmit information. The reduced amounts of myelin in patients with leukodystrophies causes life-altering disabilities, including motor and cognitive deficits. Hypomyelinating leukodystrophies are a subtype of leukodystrophy characterized by reduced myelin production during brain development. We focus on one type of hypomyelinating leukodystrophy: 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III-related leukodystrophy. Our group has previously identified that variations in the POLR3A, POLR3B and POLR1C genes cause this disease and made the first discoveries in understanding why and how these genetic defects cause disease. However, our quest to fully answer these questions has been significantly impaired by the fact that until recently, no representative animal model has existed to study this complex disease. Our team has addressed this need by generating two mouse models of 4H leukodystrophy, which will enable us to study both how the disease works and test potential treatments. We have shown that our mouse models exhibit most symptoms of the disease, including reduced myelin, tremor, and an unsteady gait. We propose to thoroughly study these mouse models, along with new ones, to understand how the observed abnormalities in myelination and neurodegeneration occur. We will also test therapeutic approaches, aiming to treat our mouse models to restore their symptoms. Ultimately, our goal is to provide a foundation upon which to develop the first treatments for children with this disorder.