Failed Parkinson's Disease Drugs Function Differently in Cell Culture Studies

By using cultures of neurons generated from induced pluripotent stem cells (iPSCs) derived from Parkinson's disease (PD) patients and presymptomatic individuals, researchers established a controllable microenvironment in which to test candidate drugs for treatment of the disease.

Investigators at Johns Hopkins University (Baltimore, MD, USA) analyzed neural cells generated from iPSCs derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. They measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria.

They reported in the July 4, 2012, issue of the journal Science Translational Medicine that neurons generated from PD patients were more susceptible to biostressors, such as the pesticide rotenone due to deficiency of functional mitochondria and over production of damaging oxygen-free radicals. The cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued by treatment with coenzyme Q10, rapamycin, or the LRRK2 kinase inhibitor GW5074. These results differed from those obtained in studies carried out in PD patients where the same drugs failed to bring about any improvement in PD symptoms.

“Our study suggests that some failed drugs should actually work if they were used earlier, and especially if we could diagnose PD before tremors and other symptoms first appear,” said contributing author Dr. Ted M. Dawson, professor of neurology at Johns Hopkins University. “This suggests the need to treat people before they actually manifest the disease. However, this work is at its earliest stages, and that application of the findings may be years away.”

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