CHIP: A Link between Parkin and Cell Death.

An autosomal recessive form of juvenile Parkinsonism (ARJP) is the major cause of early-onset Parkinson’s disease (PD) which results from mutations of the PARK2 (parkin) gene. Parkin is an E3 ubiquitin ligase that is responsible for the addition of poly-ubiquitin chains on specific substrates, which is recognized by the proteasome for degradation. Most disease-causing mutations of parkin are thought to be loss of function-mutations, leading to the failure of parkin substrates to be ubiquitinated and degraded by the proteasome. The subsequent accumulation of these substrates may ultimately cause the neuronal degeneration in ARJP. To date, nine putative substrates degraded by parkin have been reported. CHIP (carboxyl terminus of Hsc70-interacting protein), like parkin, has ubiquitin ligase activity; however, despite this common function, their client-binding domains are quite different in that parkin possesses a classical RING-finger motif whereas CHIP contains a U-box domain, conferring different substrate specificities. Although these differences in substrate recognition do exist, CHIP has been shown to modulate two parkin substrates, p38 and Pael-R, both of which have been implicated in loss of dopaminergic neurons. Whether this activity is through a direct or indirect interaction has yet to be determined; however evidence has emerged suggesting that CHIP serves an agonistic function for parkin activity, enhancing the ubiquitination of its substrates. In addition, while CHIP has a definitive relationship with the HSP70/HSP90 chaperone cycle, a similar interaction has yet to be established for parkin. Thus it is possible that CHIP mediates any crosstalk between parkin and the classical chaperone cascade. Indeed, recent work from our laboratory using CHIP knockout mice has shown that the levels of parkin increase in a gene dose-dependent manner and levels of the parkin substrate, p38, are also elevated. While several investigators have generated parkin knockout mice in an attempt to mimic ARJP in a mouse model, these mice lack frank nigral neuronal loss and therefore an appropriate model for this juvenile-onset disease has yet to be developed. Based on the above results, we suggest that the neurodegeneration expected in parkin knockout mice is perhaps mitigated by CHIP. We hypothesize that parkin and CHIP share common pathologically relevant substrates such as p38, and postulate that CHIP is a key factor in the regulation of either parkin degradation, its activity or both. Thus CHIP dysfunction in PD may precipitate disruption of the typical response to proteotoxic stress and prevent proper regulation of either parkin itself or its substrates.