. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17510-5. PubMed.


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  1. The new paper by Lo Bianco et al. marks a significant addition to their work with α-synuclein vectors and a breakthrough as the first example of an effective treatment against neurodegeneration evoked by viral vectors carrying toxic genes. Though several treatments have been shown to counteract neurotoxin lesioning, and some have been developed for Parkinson disease trials, none of them, including delivery of GDNF—as this group has shown in previous studies—has been reported to be effective in such vector models. Lo Bianco et al. now show that lentiviral delivery of parkin can have therapeutic value. These viral vector models of disease are new and we can expect that they will play an important role in selecting agents for human trials in the future.

    The increase in hyperphosphorylated aggregates in the parkin-treated animals is intriguing, although confirmation of the microscopic analysis with Western blots would have been even more convincing. It remains unclear if the neuroprotective action of parkin is related to its ubiquitin ligase activity, or if the effect of parkin is specific for α-synuclein. In this regard, we are currently testing parkin against mutant tau gene transfer, which results in behaviorally significant substantia nigra degeneration (submitted manuscript).

  2. This elegant paper extends observations previously made in tissue culture (Petrucelli et al., 2002; Oluwatosin-Chigbu et al., 2003; Chung et al., 2004) and Drosophila (Yang et al., 2003; Haywood and Stavely, 2004) models of α-synuclein toxicity, namely that parkin can suppress neuronal damage. There are several advantages to the model used by Lo Bianco et al. Here, lentiviruses are used to deliver a chronic, in vivo exposure to α-synuclein that this group has previously shown to induce selective nigral degeneration in a vertebrate animal. Therefore, it is gratifying to see that the experiment first performed in vitro has now worked in this more stringent, and hopefully, more physiologically relevant context.

    However, I think there are several valid concerns about the interpretation of all of these results (especially including our own work!). The major issue is that the mechanism involved is not yet clarified. Assuming we accept that parkin does affect α-synuclein toxicity, why does it do so? Parkin is known to be a ubiquitin-protein ligase, so one would assume that this E3 activity is required for protection. Several of the in vivo studies have skipped this important control, presumably to reduce the experimental complexity and associated cost. But I think this is a mistake—if the neuroprotective action is unrelated to E3 ligase function, then it probably isn’t related to human disease. One would be concerned if any E3-ligase had the same effect, or if it related to overexpression rather than physiological function. This could be addressed by using negative controls of inactive parkin.

    An important aspect of the model used by Lo Bianco is that these rats form α-synuclein positive intracellular inclusions that are presumably related to Lewy pathology. Perhaps surprisingly, the expression of parkin enhances the formation of these pathologies. This observation implies that inclusion body formation is beneficial and that by shunting α-synuclein into sequestered compartments, the cell can reduce its toxicity as suggested elsewhere (e.g., Olanow et al., 2004). However, it has been argued that space-filling lesions are also likely to be damaging to neurons over time (see Giasson and Lee, 2003, for a critical discussion of this issue). The significance of the model used by Lo Bianco et al. is that it gives us a way to tackle some really difficult problems. What aggregation state of α-synuclein is toxic? And is parkin disease related to PD at all or is it merely one route amongst many by which nigral neurons can die?


    . S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science. 2004 May 28;304(5675):1328-31. PubMed.

    . Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 2004 Apr 16;5:14. PubMed.

    . Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 2004 Aug;3(8):496-503. PubMed.

    . Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. Biochem Biophys Res Commun. 2003 Sep 26;309(3):679-84. PubMed.

    . Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002 Dec 19;36(6):1007-19. PubMed.

    . Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol. 2002 May;160(5):1655-67. PubMed.

    . Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron. 2003 Mar 27;37(6):911-24. PubMed.

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