Linked Life Data

12783850

Source:http://linkedlifedata.com/resource/pubmed/id/12783850

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2003-6-4
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0964-6906
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
12
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1427-37
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12783850-Adult, pubmed-meshheading:12783850-Amino Acyl-tRNA Synthetases, pubmed-meshheading:12783850-Animals, pubmed-meshheading:12783850-COS Cells, pubmed-meshheading:12783850-Carrier Proteins, pubmed-meshheading:12783850-Cell Death, pubmed-meshheading:12783850-Cercopithecus aethiops, pubmed-meshheading:12783850-Humans, pubmed-meshheading:12783850-Inclusion Bodies, pubmed-meshheading:12783850-Lewy Bodies, pubmed-meshheading:12783850-Mesencephalon, pubmed-meshheading:12783850-Mutation, pubmed-meshheading:12783850-Nerve Degeneration, pubmed-meshheading:12783850-Neuroblastoma, pubmed-meshheading:12783850-Parkinson Disease, pubmed-meshheading:12783850-Saccharomyces cerevisiae, pubmed-meshheading:12783850-Two-Hybrid System Techniques, pubmed-meshheading:12783850-Ubiquitin, pubmed-meshheading:12783850-Ubiquitin-Protein Ligases, pubmed-meshheading:12783850-p38 Mitogen-Activated Protein Kinases
pubmed:year
2003
pubmed:articleTitle
The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration.
pubmed:affiliation
INSERM U289, Hôpital de la Salpêtrière, Bâtiment Pharmacie, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't