Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons

Hong Lin, Jinbin Zhai, Zhenying Nie, Junhua Wu, Judy L. Meinkoth, William W. Schlaepfer, Rafaela Cañete-Soler

Research output: Contribution to journalArticle

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Abstract

The mechanisms whereby mutant gene expression triggers neurodegeneration are poorly understood but have generally been attributed to translated gene products. We now demonstrate direct neuropathic effects of untranslated RNA on cultured motor neurons. We show that expression of untranslated light neurofilament (NF-L) RNA sequence in the 3′UTR of an EGFP transgene (pEGFP/NF-L RNA) or in a separate expression vector (pRc/NF-L RNA) causes dose-dependent, neuron-specific motor neuron degeneration. Neither unfused EGFP protein (pEGFP/wt) nor EGFP-tagged NF-L protein (pEGFP/NF-L protein) has similar neuropathic effects. The findings are the first demonstration of a direct RNA-mediated neurotoxic effect. Moreover, the resulting neuropathological changes show that untranslated RNA can lead to early degeneration of neuritic processes and accumulations of ubiquitinated aggregates in the perikarya and nuclei of degenerating motor neurons. The latter findings are hallmark neuropathological features of neurodegenerative diseases and their occurrence as a result of altered RNA expression raises the prospects of an RNA-mediated component in the pathogenesis of neurodegenerative states.

Original languageEnglish (US)
Pages (from-to)936-950
Number of pages15
JournalJournal of Neuropathology and Experimental Neurology
Volume62
Issue number9
DOIs
StatePublished - Sep 1 2003

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Keywords

  • Motor neuron degeneration
  • Neurofilament RNA
  • Neuropathological changes
  • Primary motor neuron cultures
  • RNA-mediated neurotoxicity
  • Ubiquitinated neuronal inclusions

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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