. Synaptic vesicles: half full or half empty?. Neuron. 2006 Sep 7;51(5):523-4. PubMed.

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  1. Dopaminergic cells represent the major class of neurons lost in Parkinson disease. The unique ability of dopamine and its reactive metabolites to foster oxidative stress and protein modification has led many researchers to focus on the potential role of the dopamine molecule as an intraneuronal toxin. Previous work has implicated dopamine in the aggregation of α-synuclein (Conway et al., 2001), the neurotoxicity associated with α-synuclein overexpression (Xu et al., 2002), and the aggregation and inactivation of parkin (LaVoie et al., 2005). It has been demonstrated in vitro that α-synuclein aggregates may facilitate leakage of small molecules out of synthetic vesicles, perhaps in some pore-forming conformation (Volles et al., 2001). The implications of this model are that dopaminergic neurons might not efficiently sequester cytosolic dopamine in the presence of increased or mutant α-synuclein. This could lead to increased cytosolic dopamine levels and perhaps oxidative stress, selectively within dopamine neurons. However, the direct demonstration of altered dopamine homeostasis was not feasible until the recent advances made by Dave Sulzer’s group at Columbia. Eugene Mosharov, a postdoc in the Sulzer lab, developed a technique, referred to as intracellular patch electrochemistry (IPE), designed to estimate intracellular concentrations of catecholamines (Mosharov et al., 2003). This clever merging of patch-clamp electrophysiological techniques and carbon fiber electrochemistry allows for reliable determinations of intracellular (cytosolic) catecholamine levels, as well as the tracking of dynamic changes in dopamine levels in response to pharmacologic or stressful stimuli. In the past, this data could only have been estimated, indirectly, by dopamine turnover rates measured from ground tissue.

    The Sulzer group have now turned their attention to matters relevant to Parkinson disease. Familiar with the hypothesis that α-synuclein might permeabilize vesicles and alter cytoplasmic dopamine, they took on the admirable challenge of testing this hypothesis not only in living cell cultures, but also using in vivo models of α-synuclein overexpression. Mosharov et al. (2006) report that overexpression of α-synuclein in dopaminergic PC12 cells is associated with significant increases in cytosolic catecholamines. This effect could not be explained by changes in the enzymes responsible for dopamine synthesis or metabolism, pointing toward a homeostatic alteration.

    The authors were also able to show similar changes in peripheral, dopamine-producing tissues in α-synuclein transgenic mice, and replicate earlier findings with recombinant α-synuclein protein with respect to α-synuclein-induced proton leakage across chromaffin granules. Surprisingly, however, the wild-type transgenic α-synuclein mice did not show altered catecholamine levels despite expression levels of α-synuclein that were equal to or greater than the A30P mice. Therefore, not all aspects of the paper fully support the hypothesis; however, the authors provide a very balanced discussion highlighting important consistencies as well as caveats.

    It should be noted that in the PC12 cell culture experiments, both the A30P and A53T variants had greater effects on cytosolic catecholamine levels than did wild-type α-synuclein. This trend is consistent with the aggregation rates of these α-synuclein isoforms (Conway et al., 1998), as well as their reported ability to permeabilize synthetic vesicles in vitro (Volles and Lansbury, 2002). This aspect of the current paper strongly suggests that the authors have the story right. They have demonstrated an interesting property of α-synuclein in cultured cells with broad implications as to the redox status specifically within dopaminergic neurons with respect to α-synuclein levels. Overproduction or decreased turnover of wild-type or mutant α-synuclein might increase cytosolic dopamine, inducing oxidative stress, as well as the covalent modification of thiol-dependent proteins such as parkin (LaVoie et al., 2005), resulting in cell death.

    While support for the dopamine hypothesis in Parkinson disease certainly appears to be gaining some momentum, it should also be remembered that several non-dopaminergic nuclei are affected in this disorder. Therefore, many other factors are likely involved, and hopefully the near future will uncover important clues as to what other molecular events may participate in the neurodegenerative process within the parkinsonism brain.

    View all comments by Matthew LaVoie
  2. Speaking of α-synuclein, Kim and colleagues (1) report that Dyrk1A, a dual-specificity tyrosine-regulated kinase can phosphorylate α-synuclein and that aggregates formed by phosphorylated α-synuclein are more neurotoxic compared with aggregates composed of unmodified wild-type α-synuclein. Increased Dyrk1A immunoreactivity has been found in the cytoplasm and nuclei of scattered neurons of the neocortex, entorhinal cortex, and hippocampus in AD, DS, and Pick Disease (2).

    It would be interesting to see whether there was a reduction in Lewy bodies with the use of the Dyrk1A inhibitor - (-)-epigallocatechin gallate, (EGCG), a polyphenol found in green tea. Perhaps this may explain the neuroprotective effect of EGCG in Parkinson models.

    View all comments by Mary Reid

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