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Kalia SK, Lee S, Smith PD, Liu L, Crocker SJ, Thorarinsdottir TE, Glover JR, Fon EA, Park DS, Lozano AM. BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron. 2004 Dec 16;44(6):931-45. PubMed.
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National Institute on Aging
The experiments presented by the Lazano group are solid because the authors have been careful to cover as many bases as they can to test their major hypothesis: that BAG5 is a natural inhibitor of parkin function. But as well as being careful science, the study is interesting for two reasons. Firstly, along with recent data from several other groups, this reinforces the idea that parkin is a generally good neuroprotective protein for nigral neurons. In this particular case, the link to the E3 ligase function of parkin is strengthened because BAG5 appears to decrease parkin’s enzyme activity. That this is specific is demonstrated by the use of the DARA-BAG5 construct that is expressed but cannot bind to its targets, parkin and Hsp70. Secondly, the role of Hsp70 is highlighted by the observation that BAG5 antagonizes the previously identified interaction of this chaperone with parkin (Imai et al., 2002).
This makes me wonder about the exact role of Hsp70. Hsp70 could be unfolding substrates for parkin and/or moving them from insoluble to more soluble fractions, enhancing their ability to be recognized by parkin. Alternatively—and the Kalia et al. paper provides evidence for this—Hsp70 may be important in maintaining a stable, soluble pool of active parkin. The distinction between these two ideas may seem minor: In either case, the presence of Hsp70 makes for more parkin activity and BAG5 would prevent this. But it has some implications for how we interpret studies in which we rely on the overexpression of parkin to protect cells. Is the effect really due to parkin being an E3 ligase, or is it sequestering some of its toxic proteins in the insoluble fraction because parkin itself is prone to misfolding and tends to make inclusion bodies? The paper by Kalia et al. provides the impression that one has to have active, soluble, and folded parkin for neuroprotection, even if sequestration of damaging substrates into the insoluble fraction is a beneficial mechanism by itself.
References:
Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R. CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell. 2002 Jul;10(1):55-67. PubMed.
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