biostudies-literatureMoir RDNICHD NIH HHSNINDS NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSRP95314https://www.ebi.ac.uk/biostudies/studies/S-EPMC11537486biostudies-literatureUnknown13Pathogenic 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 progreseLifeMolecular basis of neurodegeneration in a mouse model of &lt;i&gt;Polr3&lt;/i&gt;-related disease.PMC11537486R01 NS129951U54 HD090260P30 CA013330R21 NS123730S10 OD023591S10 OD026852P50 HD105352RO1 NS129951Merheb EMoir RDStanley ERChitu VWillis IMfalseMolecular basis of neurodegeneration in a mouse model of &lt;i&gt;Polr3&lt;/i&gt;-related disease.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 progres2024-01-01T00:00:00Z2024 Nov2026-05-04T06:42:21.079Z2025-04-06T10:11:24.392ZS-EPMC115374863949964510.7554/eLife.95314