Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins

Dong Hoon Hyun, Moon Hee Lee, Barry Halliwell, Peter Jenner

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Mutations in Cu,Zn-superoxide dismutase (SOD-1) are associated with some familial cases of amyotrophic lateral sclerosis (ALS), but it is not known how they result in cell death. We examined effects of overexpression of wild-type SOD-1 or the G37R or G85R mutations on the accumulation of ubiquitinated and nitrated proteins, and on loss of cell viability induced by the proteasome inhibitor, lactacystin. Wild-type SOD-1 had no effect on proteasomal activity, but the mutants decreased it somewhat. Treatment with lactacystin (1 μM) caused only limited cell viability loss, even though it induced a marked inhibition of proteasomal activities. However, viability loss due to apoptosis was substantial in response to lactacystin when cells were overexpressing a mutant SOD-1. The frequency of cells showing immunoreactivity against ubiquitinatedor nitrated-proteins was enhanced when wild-type and mutant SOD-1 s were overexpressed. Ubiquitinated or nitrated α-tubulin, SOD-1, α-synuclein and 68K neurofilaments were observed in the aggregates. Similar aggregates were observed in cells overexpressing mutant parkin (Del3-5, T240R and Q311'X). The nitric oxide synthase inhibitor, L-NAME, decreased viability loss and aggregation, suggesting that nitration of proteins may play an important role in aggregation and in the cell death accompanying it.

Original languageEnglish
Pages (from-to)363-373
Number of pages11
JournalJournal of Neurochemistry
Volume86
Issue number2
DOIs
StatePublished - Jul 2003

Keywords

  • Aggregates
  • Amyotrophic lateral sclerosis
  • Lactacystin
  • Proteasomal inhibition
  • Protein nitration
  • SOD-1

Fingerprint

Dive into the research topics of 'Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins'. Together they form a unique fingerprint.

Cite this