The wrong suspect?

P atients with Parkinson's disease (PD) suffer a specifi c loss of dop-aminergic neurons from the mid-brain region that controls motor function. The exact mechanism of this selective neurodegeneration is unclear, though many lines of evidence point to dysfunctional mitochondrial complex I as one root cause of the disease. Yet Choi et al. now suggest that defective regulation of micro-tubules may be responsible for at least some cases of PD (1). Mitochondria were fi rst implicated in PD when drug users in California developed Parkinson's-like symptoms due to a contaminant in their heroin supply called MPTP (2). This chemical is metabolized in the brain into MPP + , a compound that blocks oxidative phosphorylation by inhibiting mitochondrial complex I. Subsequently, other chemicals such as rotenone were shown to inhibit complex I and induce PD in animal models, and PD patients were found to have reduced levels of complex I activity. Moreover, several proteins linked to genetic forms of PD are involved in maintaining normal mitochondrial function (3). But in 2008, Zhengui Xia and colleagues at the University of Washington in Seattle began to cast doubt on complex I's guilt (4). " We didn't set out to prove anybody wrong, " says Xia. " We just wanted to do a quick experiment to provide genetic proof that complex I inhibition causes dopaminergic neuron death. " Xia and colleagues therefore examined mice lacking an essential subunit of complex I called Ndufs4. To their surprise, dopaminergic neurons from these mice were healthy and remained sensitive to MPP +-and rotenone-induced death (4). This suggested that complex I inhibition is insuffi cient to cause dopaminergic nerve apoptosis. Confi rming this, Choi et al. found that another complex I inhibitor, piericidin A, has no effect on dopaminergic cell survival (1). " So if it's not by inhibiting complex I, what is the mechanism [by which rotenone and other drugs kills these neurons]? " says Xia. The researchers turned their attention to another property of rotenone: the drug also depolymerizes microtubules. Cultured dop-aminergic neurons were spared from rote-none-induced death if they were co-treated with the microtubule-stabilizing drug taxol. On the other hand, the depolymerizing agent colchicine was as deadly as rotenone to dopamine-producing neurons. But why do these microtubule-disrupting drugs only kill dopaminergic neurons and not other types of nerve cells? " Microtu-bule disassembly impairs dopamine release , so dopamine accumulates in the cell, " explains Xia. …