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Human Molecular Genetics, 2003, Vol. 12, No. 12 1427-1437
DOI: 10.1093/hmg/ddg159
© 2003 Oxford University Press

The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration

Olga Corti1,{dagger}, Cornelia Hampe1,{dagger}, Hana Koutnikova1, Frédéric Darios1, Sandrine Jacquier1, Annick Prigent1, Jean-Charles Robinson2, Laurent Pradier3, Merle Ruberg1, Marc Mirande2, Etienne Hirsch1, Thomas Rooney3, Alain Fournier3 and Alexis Brice1,*

1INSERM U289, Hôpital de la Salpêtrière, Bâtiment Pharmacie, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France, 2Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, 91190 Gif-sur-Yvette, France and 3CNS Department and Yeast Genomics, Aventis-Pharma, 94400 Vitry, France

Received January 22, 2003; Revised April 4, 2003; Accepted April 22, 2003

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.

* To whom correspondence should be addressed. Tel: +33 142162183; Fax: +33 144243658; Email: brice{at}ccr.jussieu.fr

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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