TorsinA dysfunction causes persistent neuronal nuclear pore defects

Samuel S. Pappas, Chun Chi Liang, Sumin Kim, Chey Anne O. Rivera, William T. Dauer

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

A critical challenge to deciphering the pathophysiology of neurodevelopmental disease is identifying which of the myriad abnormalities that emerge during CNS maturation persist to contribute to long-termbrain dysfunction. Childhood-onset dystonia caused by a loss-of-function mutation in the AAA+ protein torsinA exemplifies this challenge. Neurons lacking torsinA develop transient nuclear envelope (NE) malformations during CNS maturation, but no NE defects are described in mature torsinA null neurons. We find that during postnatal CNS maturation torsinA null neurons develop mislocalized and dysfunctional nuclear pore complexes (NPC) that lack NUP358, normally added late in NPC biogenesis. SUN1, a torsinA-related molecule implicated in interphase NPC biogenesis, also exhibits localization abnormalities. Whereas SUN1 and associated nuclear membrane abnormalities resolve in juvenile mice, NPC defects persist into adulthood. These findings support a role for torsinA function in NPC biogenesis during neuronal maturation and implicate altered NPC function in dystonia pathophysiology.

Original languageEnglish (US)
Pages (from-to)407-420
Number of pages14
JournalHuman molecular genetics
Volume27
Issue number3
DOIs
Publication statusPublished - Feb 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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