Pol III-associated leukodystrophy is an autosomal recessive neurodegenerative disease linked to mutations in subunits of RNA polymerase III (Pol III). The clinical and radiologic spectrum of the disorder has only recently been defined. Pol III-associated leukodystrophy is characterized by hypomyelination of cerebral white matter and presents as a progressive decline in motor function, developmental delay and intellectual disability. Disease onset typically occurs during childhood but the age range at diagnosis is broad, reflecting the variable severity and slow progression of the disease. Other clinical characteristics include myopia, hypodontia and endocrine abnormalities but these features are not always present. The mechanism of pathogenesis is unknown and no therapeutic options are available. Further progress in understanding this disease is limited by the lack of model systems. Thus, the goal of this research is to develop a mouse model of Pol III-associated leukodystrophy. We have created a knock-in mouse expressing clinically-defined Pol III-associated leukodystrophy mutations. We will characterize the behavioral, radiologic and neuropathologic phenotypes of these mice. Phenotypic changes will be correlated with the impact of the mutation on Pol III transcription, tRNA biogenesis and protein synthesis. In addition, we will test a model for genetic suppression of Pol III-associated leukodystrophy phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-associated leukodystrophy and will provide a model system for testing therapeutic approaches targeting the disease.
Pol III-associated leukodystrophy is a progressive and untreatable neurodegenerative disease characterized by hypomyelination, loss of motor function, cognitive defects and variable additional phenotypes. We have generated a mouse model of Pol III-associated leukodystrophy to enable studies on the mechanisms of disease pathogenesis. In this work we will test the hypothesis that decreased transcription of small non- coding RNAs by Pol III leads to defects in protein synthesis in the brain and impairs neuronal function. In addition, to inform therapeutic approaches, we will test a genetic mechanism for suppressing Pol III-associated leukodystrophy phenotypes in the mice.
