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Dopamine, Alpha-synuclein, and autophagic cell death

Daniela F Hernandez, MA, MPhil, PhD candidate, Columbia University
Dopamine , PARK1/4 (SNCA/Alpha-Synuclein), Oxidative Stress
Response to Discussion:
How can oxidative stress contribute to alpha-synuclein pathology/toxicity? What oxidative modifications of alpha-synuclein are relevant to the PD pathogenic process?
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Elevated cytosolic DA levels have been shown to result in increased neurotoxicity in cellular models of PD (Mosharov et al., 2009). In a new study published in the Journal of Neuroscience Research, Gomez-Santos and colleagues confirm these findings in PC12 cells.  They show that extracellular application of DA leads to a dose-dependent decrease in cell viability and to an increase in alpha-synuclein expression mediated at least in part by activation of p38.  They also show that exposure to DA increases the number of autophagic vacuoles and that treatment with 3-MA, an autophagy inhibitor, was protective against DA-mediate cell death. Treatment with nomifensine, a DAT inhibitor, and with antioxidants was also protective.  It would be interesting to test whether treatment with nomifensine and antioxidants prevents the increase in alpha-synuclein expression and to examine by what mechanism p38 and autophagy inhibition result in a decrease in alpha-synuclein expression as reported in this study.

Reference: 
Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron. 2009;62(2):218-29.
Gómez-Santos C, Ferrer I, Santidrián AF, Barrachina M, Gil J, Ambrosio S. Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res. 2003;73(3):341-50.
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