Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons

Woo Yang Kim, Craig Horbinski, Wade Sigurdson, Dennis Higgins*

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

At least nine neurodegenerative disorders are caused by expansion of polyglutamine repeats in various genes. This expansion induces the formation of nuclear inclusions (NI) within various cell types. In this study, we developed a model for polyglutamine diseases using primary cultures of sympathetic neurons from the superior cervical ganglia of prenatal rat pups. Transfection with a plasmid encoding 127 glutamine repeats causes NI to develop in ∼70% of the sympathetic neurons within 6 days. In addition, it causes somatic atrophy and inhibits dendritic growth. The NIs contain ubiquitinated proteins and sequester the molecular chaperone heat shock protein 70 (Hsp70). We found that two specific proteasome inhibitors, lactacystin and CEP1612, suppress thezformation of polyglutamine-induced NI. In addition, lactacystin treatment induced the removal of preexisting NI. Western blotting and immunocytochemistry revealed that lactacystin and CEP1612 strongly induce the expression of Hsp70, whereas less specific proteasome inhibitor such as N-acetyl-Leu-Leu-Norleucinal does not. Coexpression of 127 glutamines with a plasmid encoding wild-type Hsp70 gene resulted in a marked reduction of the percentage of neurons containing NI. In addition, transfection with plasmids encoding mutant Hsp70 blocked the effects of lactacystin. These findings further implicate Hsp70 as a neuroprotective molecule and they suggest the potential utility of certain proteasome inhibitors in the treatment of polyglutamine diseases.

Original languageEnglish (US)
Pages (from-to)1044-1056
Number of pages13
JournalJournal of neurochemistry
Volume91
Issue number5
DOIs
StatePublished - Dec 1 2004

Keywords

  • Heat shock protein 70
  • Molecular chaperone
  • Nuclear inclusion
  • Polyglutamine diseases
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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