RT Journal Article
SR Electronic
T1 α-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9304
OP 9311
DO 10.1523/JNEUROSCI.0519-06.2006
VO 26
IS 36
A1 Eugene V. Mosharov
A1 Roland G. W. Staal
A1 Jordi Bové
A1 Delphine Prou
A1 Anthonia Hananiya
A1 Dmitriy Markov
A1 Nathan Poulsen
A1 Kristin E. Larsen
A1 Candace M. H. Moore
A1 Matthew D. Troyer
A1 Robert H. Edwards
A1 Serge Przedborski
A1 David Sulzer
YR 2006
UL http://www.jneurosci.org/content/26/36/9304.abstract
AB Dysregulation of dopamine homeostasis and elevation of the cytosolic level of the transmitter have been suggested to underlie the vulnerability of catecholaminergic neurons in Parkinson’s disease. Because several known mutations in α-synuclein or overexpression of the wild-type (WT) protein causes familial forms of Parkinson’s disease, we investigated possible links between α-synuclein pathogenesis and dopamine homeostasis. Chromaffin cells isolated from transgenic mice that overexpress A30P α-synuclein displayed significantly increased cytosolic catecholamine levels as measured by intracellular patch electrochemistry, whereas cells overexpressing the WT protein and those from knock-out animals were not different from controls. Likewise, catechol concentrations were higher in l-DOPA-treated PC12 cells overexpressing A30P or A53T compared with those expressing WT α-synuclein, although the ability of cells to maintain a low cytosolic dopamine level after l-DOPA challenge was markedly inhibited by either protein. We also found that incubation with low-micromolar concentrations of WT, A30P, or A53T α-synuclein inhibited ATP-dependent maintenance of pH gradients in isolated chromaffin vesicles and that the WT protein was significantly less potent in inducing the proton leakage. In summary, we demonstrate that overexpression of different types of α-synuclein disrupts vesicular pH and leads to a marked increase in the levels of cytosolic catechol species, an effect that may in turn trigger cellular oxyradical damage. Although multiple molecular mechanisms may be responsible for the perturbation of cytosolic catecholamine homeostasis, this study provides critical evidence about how α-synuclein might exert its cytotoxicity and selectively damage catecholaminergic cells.