Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death.
Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.
Ko
Han Seok
HS
Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
von Coelln
Rainer
R
Sriram
Sathya R
SR
Kim
Seong Who
SW
Chung
Kenny K K
KK
Pletnikova
Olga
O
Troncoso
Juan
J
Johnson
Brett
B
Saffary
Roya
R
Goh
Eyleen L
EL
Song
Hongjun
H
Park
Bum-Joon
BJ
Kim
Min Jung
MJ
Kim
Sunghoon
S
Dawson
Valina L
VL
Dawson
Ted M
TM
D000604:Amino Acyl-tRNA Synthetases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002395:Catecholamines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D003067:Coenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D013379:Substrate Specificity / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002395:Catecholamines; D003067:Coenzymes; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048051:p38 Mitogen-Activated Protein Kinases; D000604:Amino Acyl-tRNA Synthetases