A new in-vitro model of Parkinson's disease, induced by the pesticide rotenone, appears to recapitulate much of the cellular pathology that marks the neurodegenerative disease. The important difference from previous similar studies, say the authors of the Journal of Neuroscience article, was the use of chronic, low-level exposure to the toxin.
Rotenone is one of several toxins that can produce a parkinsonian condition in vivo, including both selective destruction of substantia nigra dopaminergic (DA) neurons and accumulation of insoluble α-synuclein inclusions (Lewy bodies) in DA neurons. The mechanism for this effect is not clear, but one of the well-known effects of rotenone is to interfere with complex I of the mitochondrial electron transfer chain, and complex I activity is known to be decreased in PD.
In their new model of rotenone exposure, -Timothy Greenamyre, Todd Sherer and colleagues at Emory University in Atlanta, Georgia, and the U.S. National Institute on Aging in Bethesda, Maryland, maintained human neuroblastoma cells in culture with 5 nM rotenone. At four weeks, the cells appeared normal, but about 5 percent had begun to undergo apoptosis. In addition, levels of insoluble α-synuclein and ubiquitin (another component of Lewy bodies) increased. The cells also showed evidence of oxidative stress, including decreased glutathione and signs of oxidative damage to DNA and proteins.
Even more dramatic was the manner in which the chronic treatment appeared to weaken the cells to further oxidative damage. The researchers challenged the cells with H2O 2, an oxidative species that is abundant in dopaminergic cells as a byproduct of dopamine metabolism. The rotenone-sensitized cells released more cytochrome C from mitochondria, activated caspase-3, and increased apoptosis relative to untreated cells.
The authors point out one significant limitation of the study, namely that the cells used were not dopaminergic neurons, which are notoriously difficult to keep alive for chronic in-vitro study. Nevertheless, the authors believe that further experiments in this model will allow them to define the sequence of cellular responses to chronic complex I inhibition, probe for links to the pathology of PD, and screen potential therapeutics.—Hakon Heimer