Molecular basis of neurodegeneration in a mouse model of <i>Polr3</i>-related disease.

Abstract

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of <i>Polr3</i>-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of <i>Polr3</i>-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic <i>Polr3a</i> mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. <i>Polr3a</i> mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.