Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis
Open Access
- 24 October 2000
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 97 (23), 12571-12576
- https://doi.org/10.1073/pnas.220417997
Abstract
Deposition of aggregated protein into neurofilament-rich cytoplasmic inclusion bodies is a common cytopathological feature of neurodegenerative disease. How—or indeed whether—protein aggregation and inclusion body formation cause neurotoxicity are presently unknown. Here, we show that the capacity of superoxide dismutase (SOD) to aggregate into biochemically distinct, high molecular weight, insoluble protein complexes (IPCs) is a gain of function associated with mutations linked to autosomal dominant familial amyotrophic lateral sclerosis. SOD IPCs are detectable in spinal cord extracts from transgenic mice expressing mutant SOD several months before inclusion bodies and motor neuron pathology are apparent. Sequestration of mutant SOD into cytoplasmic inclusion bodies resembling aggresomes requires retrograde transport on microtubules. These data indicate that aggregation and inclusion body formation are mechanistically and temporally distinct processes.Keywords
This publication has 45 references indexed in Scilit:
- Aggresomes: A Cellular Response to Misfolded ProteinsThe Journal of cell biology, 1998
- Aggregation and Motor Neuron Toxicity of an ALS-Linked SOD1 Mutant Independent from Wild-Type SOD1Science, 1998
- Frameshift Mutants of β Amyloid Precursor Protein and Ubiquitin-B in Alzheimer's and Down PatientsScience, 1998
- Structural Neurology: Are Seeds at the Root of Neuronal Degeneration?Neuron, 1997
- ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing InclusionsNeuron, 1997
- Breakdown of oxidized proteins as a part of secondary antioxidant defenses in mammalian cellsBioFactors, 1997
- Proteasome inhibition enhances the stability of mouse CuZn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosisJournal of the Neurological Sciences, 1996
- Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injuryNature Genetics, 1996
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993
- Serial analysis of microtubules in cultured rat sensory axonsJournal of Neurocytology, 1981