The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration
Abstract
Parkinson's disease (PD) is a severe neurological disorder, characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the presence of Lewy bodies (LBs). The discovery of genes responsible for familial forms of the disease has provided insights into its pathogenesis. Mutations in the parkin gene, which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, have been found in nearly 50% of patients with autosomal-recessive early-onset parkinsonism. The abnormal accumulation of substrates due to loss of Parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. Here, we demonstrate that Parkin interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian aminoacyl-tRNA synthetase complex. We found that the ubiquitylation of p38 is abrogated by truncated variants of Parkin lacking essential functional domains, but not by the pathogenic Lys161Asn point mutant. Expression of p38 in COS7 cells resulted in the formation of aggresome-like inclusions in which Parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, Parkin promoted the formation of ubiquitylated p38-positive inclusions. Moreover, the overexpression of p38 in SH-SY5Y cells caused significant cell death against which Parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of LBs in idiopathic PD. This suggests that p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration.
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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Aggresomes: A Cellular Response to Misfolded Proteins
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Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
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“We next evaluated whether the deletion of the functional domains involved in the E3 ubiquitin–protein ligase activity of Parkin affects the Parkin-mediated ubiquitylation of p38 in SHSY5Y cells (19,20).”
BackgroundJoazeiro, C. A. P., & Weissman, A. M. (2000) · Cell · doi:10.1016/s0092-8674(00)00077-5 · Cited by 1,249
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Proteasomal function is impaired in substantia nigra in Parkinson’s disease
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Cited by
MOLECULAR PATHOPHYSIOLOGY OF PARKINSON'S DISEASE
Moore, D. J., West, A. B., Dawson, V. L., & Dawson, T. M. (2005) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.061604.135718 · Cited by 1,280
Mitochondrial Dysfunction and Oxidative Damage in parkin-deficient Mice
Palacino, J. J., Sagi, D., Goldberg, M. S., Krauss, S., Motz, C., Wacker, M., Klose, J., & Shen, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401135200 · Cited by 995
The Ubiquitin Proteasome System in Neurodegenerative Diseases
Ciechanover, A., & Brundin, P. (2003) · Neuron · doi:10.1016/s0896-6273(03)00606-8 · Cited by 982
PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease
Shin, J.-H., Ko, H. S., Kang, H., Lee, Y., Lee, Y.-I., Pletinkova, O., Troconso, J. C., Dawson, V. L., & Dawson, T. M. (2011) · Cell · doi:10.1016/j.cell.2011.02.010 · Cited by 953
Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons
Goldberg, M. S., Fleming, S. M., Palacino, J. J., Cepeda, C., Lam, H. A., Bhatnagar, A., Meloni, E. G., Wu, N., Ackerson, L. C., Klapstein, G. J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308947200 · Cited by 913
Metadata
- Authors
- Corti, O.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-06-15
- Volume
- 12
- Issue
- >12
- Pages
- 1427-1437
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2148869194
- Cited by
- 244
- References
- 10
- FWCI
- 13.67
- Type
- journal article
- Language
- en
- Open access
- closed
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