Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 17 March 2009
Vol. 2, Issue 62, p. ec103
[DOI: 10.1126/scisignal.262ec103]

EDITORS' CHOICE

Parkinson's Disease From PINK(1) to Code Red

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

Evidence that mutations in mitochondrially localized proteins, including PINK1 (PTEN-induced putative kinase 1), can cause a familial or inherited form of Parkinson’s disease has focused attention on potential roles of signaling in the mitochondria in Parkinson’s disease and in normal cell function. Gandhi et al. present studies that reveal a chain of events that may account for increased neuronal cell death in animals deficient in PINK1 that would help explain the neurodegeneration seen in Parkinson’s disease. The authors analyzed PINK1 functions by depleting PINK1 from a human dopaminergic neuroblastoma cell line with shRNA and then stably expressing either wild-type or catalytically inactive PINK1. They also confirmed results in cultured neurons derived from human stem cells or in cells from knockout mice lacking PINK1. Cells expressing catalytically inactive PINK1 had decreased mitochondrial membrane potential. This appeared to result from decreased respiration, because provision of substrates for mitochondrial complexes I and II partially restored the mitochondrial membrane potential. The lack of substrate supply also increased the abundance of the oxidized forms of NADH and FAD2+ in mitochondria lacking functional PINK1. Calcium signaling was disrupted in cells lacking PINK1 function, and physiological stimuli resulted in excessive accumulation of free calcium in the mitochondria and decreased mitochondrial membrane potential. Studies monitoring release of caged calcium in the mitochondria indicated that impaired function of PINK1 led to failure of a Na+/Ca2+ exchanger, thus preventing proper calcium efflux from the mitochondria. Increased concentrations of free calcium in the mitochondria were associated with increased production of ROS (reactive oxygen species) through activation of NADPH oxidase. Overproduction of ROS, in turn, was associated with impaired uptake of glucose, potentially explaining the decreased substrate availability noted above. The authors propose that this chain of events culminating in decreased mitochondrial membrane potential would lead to premature opening of the permeability transition pore. The opening of the permeability transition pore can have disastrous consequences—increased production of ROS, decreased respiration, and release of cytochrome c—that lead to neuronal cell death.

S. Gandhi, A. Wood-Kaczmar, Z. Yao, H. Plun-Favreau, E. Deas, K. Klupsch, J. Downward, D. S. Latchman, S. J. Tabrizi, N. W. Wood, M. R. Duchen, A. Y. Abramov, PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol. Cell 33, 627–638 (2009). [Online Journal]

Citation: L. B. Ray, From PINK(1) to Code Red. Sci. Signal. 2, ec103 (2009).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882