. 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.


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  1. This paper shows how critical it is to differentiate between observations that are real in the context in which they were found versus those that can be extrapolated to physiological situations. A previous study from Goldberg et al. failed to detect accumulation of several proteins that had been proposed to be parkin substrates largely on the basis of in vitro experiments. But in finding that, of a variety of parkin substrates, only p38 accumulates to a significant extent in parkin-null mice, Ko et al. demonstrate that some damaging substrates may really accumulate in vivo from physiological levels of expression. Furthermore, by showing that (admittedly supra-physiological) forced expression of p38 can decrease the number of tyrosine hydroxylase-positive neurons, an experiment that has already been performed for another parkin substrate CDCrel1 (Dong et al., 2003), the authors also support the hypothesis that accumulation of one or more of parkin’s substrates damages neurons in recessive parkinsonism. As it would probably be easier, pharmacologically, to inhibit the function of a substrate rather than boost the activity of parkin, this may give some clues for future therapeutics.

    This is a full and detailed study, but of course there are many future directions for the field to follow. A major question is why p38 should have selectively toxic effects on specific groups of neurons. I can’t claim any novel insight here, but Corti et al. originally pointed out that this could be either due to a failure of protein synthesis or a noncanonical function of the aminoacyl-tRNA synthetase (ARS) complex that may include cell death. Another interesting study would be to see if p38 acts alone or whether a smaller accumulation of several substrates may contribute to toxicity. Although it failed to reach significance, there is a small accumulation of CDCrel-1 in the soluble fraction in these mice. It’s possible that p38 has sufficient effect on its own, but maybe also that CDCrel-1 (or other substrates not tested here) might have additive effects.

    See also:

    Ko et al., in press.


    . The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet. 2003 Jun 15;12(12):1427-37. PubMed.

    . Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12438-43. PubMed.

    . Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003 Oct 31;278(44):43628-35. PubMed.