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Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins.
- Source :
-
Journal of neurochemistry [J Neurochem] 2003 Jul; Vol. 86 (2), pp. 363-73. - Publication Year :
- 2003
-
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 micro m) 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 ubiquitinated- or nitrated-proteins was enhanced when wild-type and mutant SOD-1 s were overexpressed. Ubiquitinated or nitrated alpha-tubulin, SOD-1, alpha-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.
- Subjects :
- Cell Line
Cell Survival drug effects
Cell Survival genetics
Cysteine Endopeptidases
Enzyme Inhibitors pharmacology
Gene Transfer Techniques
Humans
Ligases biosynthesis
Ligases genetics
Macromolecular Substances
Nerve Tissue Proteins biosynthesis
Neurofilament Proteins biosynthesis
Nitric Oxide Synthase antagonists & inhibitors
Proteasome Endopeptidase Complex
Superoxide Dismutase genetics
Superoxide Dismutase metabolism
Superoxide Dismutase-1
Synucleins
Tubulin biosynthesis
Ubiquitin metabolism
alpha-Synuclein
Acetylcysteine analogs & derivatives
Acetylcysteine pharmacology
Multienzyme Complexes antagonists & inhibitors
Nitrates metabolism
Proteins metabolism
Ubiquitin-Protein Ligases
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3042
- Volume :
- 86
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12871577
- Full Text :
- https://doi.org/10.1046/j.1471-4159.2003.01841.x