The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration.
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.
Corti
Olga
O
INSERM U289, Hôpital de la Salpêtrière, Bâtiment Pharmacie, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Hampe
Cornelia
C
Koutnikova
Hana
H
Darios
Frédéric
F
Jacquier
Sandrine
S
Prigent
Annick
A
Robinson
Jean-Charles
JC
Pradier
Laurent
L
Ruberg
Merle
M
Mirande
Marc
M
Hirsch
Etienne
E
Rooney
Thomas
T
Fournier
Alain
A
Brice
Alexis
A
D000328:Adult; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002522:Chlorocebus aethiops; D006801:Humans; D002479:Inclusion Bodies; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008636:Mesencephalon / Q000378:metabolism*; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D012441:Saccharomyces cerevisiae; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048051:p38 Mitogen-Activated Protein Kinases; D000604:Amino Acyl-tRNA Synthetases