A whole body model of Pol III-related leukodystrophy

Project Summary RNA polymerase (Pol) III-related leukodystrophy is a recently identified autosomal recessive neurodegenerative disorder that causes hypomyelination with variable disease onset and severity. The disease is usually identified during childhood based on neurological deficits that include developmental delay, cognitive regression, a progressive decline in motor function and intellectual disability. Additional clinical characteristics can include myopia, hypodontia and endocrine abnormalities. An understanding of the disease mechanisms is currently lacking and progress has been limited by the absence of an animal model. Recent work has generated a lineage-specific knock-in mouse model of Pol III-related leukodystrophy that exhibits a subset of disease features found in patients and a relatively mild disease course. However, this model lacks gross motor defects and cerebellar phenotypes that are generally associated with more severe disease. Pol III-related leukodystrophy patients express mutant Pol III subunits in all somatic cells yet the disease is predominantly limited to the central nervous system. Thus, to better model the human disease, a conditional whole-body knock-in mouse was developed. This mouse model exhibits gross motor defects and a more severe disease course. The goals of this proposal are to characterize behavioral and neuropathological phenotypes of these mice and to profile Pol III transcriptional changes in neural cell populations to develop a molecular understanding of disease pathogenesis. In addition, we will test a genetic strategy for suppression of transcriptional and disease phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-related leukodystrophy and will provide a whole-body model system for testing therapeutic approaches targeting the disease.