Molecular basis of neurodegeneration in a mouse model of Polr3-related disease

Robyn D. Moir, Emilio Merheb, Violeta Chitu, E. Richard Stanley, Ian M. Willis

Research output: Contribution to journalArticlepeer-review

Abstract

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-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 Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a 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.

Original languageEnglish (US)
JournaleLife
Volume13
DOIs
StatePublished - Nov 5 2024

Keywords

  • Polr3-related disease
  • RNA polymerase III
  • chromosomes
  • gene expression
  • innate immune response
  • integrated stress response
  • mouse
  • neurodegeneration
  • neuroscience
  • tRNA

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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