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The Journal of Neuroscience, August 31, 2005, 25(35):7968-7978; doi:10.1523/JNEUROSCI.2172-05.2005
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Neurobiology of Disease
Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death
Han Seok Ko,1,2 Rainer von Coelln,1,2 Sathya R. Sriram,1,2,6 Seong Who Kim,1,2 Kenny K. K. Chung,1,2 Olga Pletnikova,5 Juan Troncoso,2,5 Brett Johnson,1,2 Roya Saffary,1,2 Eyleen L. Goh,1,2 Hongjun Song,1,2,3,6 Bum-Joon Park,7 Min Jung Kim,7 Sunghoon Kim,7 Valina L. Dawson,1,2,3,4,6 andTed M. Dawson1,2,3,6 1Institute for Cell Engineering, Departments of 2Neurology, 3Neuroscience, 4Physiology, and 5Pathology, and 6Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and 7National Creative Research Initiatives Center for Human Aminoacyl-tRNA Synthetases Network, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
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-
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.
Key words: Parkinson's disease; parkin; ubiquitination; proteasome degradation; p38/JTV1; dopaminergic neuronal cell death
Received May 28, 2005; revised July 12, 2005; accepted July 14, 2005.
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