RT Journal Article
SR Electronic
T1 Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7968
OP 7978
DO 10.1523/JNEUROSCI.2172-05.2005
VO 25
IS 35
A1 Han Seok Ko
A1 Rainer von Coelln
A1 Sathya R. Sriram
A1 Seong Who Kim
A1 Kenny K. K. Chung
A1 Olga Pletnikova
A1 Juan Troncoso
A1 Brett Johnson
A1 Roya Saffary
A1 Eyleen L. Goh
A1 Hongjun Song
A1 Bum-Joon Park
A1 Min Jung Kim
A1 Sunghoon Kim
A1 Valina L. Dawson
A1 Ted M. Dawson
YR 2005
UL http://www.jneurosci.org/content/25/35/7968.abstract
AB 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-α 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.