Seok Ko H, von Coelln R, Sriram SR, Who Kim S, Chung KK, Pletnikova O, Troncoso J, Johnson B, Saffary R, Dawson VL.
Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death.
Journal of Neuroscience. 2005 Aug;25(35):7968.
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.