Ow! My head!

It looks like rotenone actually targets the microtubules in dopamine neurons. However I'm not very impressed by the description of the researcher that dopamine neurons are preferentially damaged because they have long microtubules. Or is it that dopamine is more oxidative when it can't be released?
I also don't understand the parkin/microtubule interaction. Do those rats have parkin mutations?

These are all variations on the same study:

Two-Fisted Assault On Dopamine Transport System May Be Foundation Of Parkinson's Disease

researcher's home page
http://www.acsu.buffalo.edu/~jianfeng/
As microtubules play obligatory functions in the maintenance of cellular morphology and intracellular transport, their depolymerization by rotenone causes significant damages to the cell, especially for long projection neurons such as dopamine cells on the nigrostriatal pathway. This is because microtubule depolymerization causes vesicle accumulation in the soma, which leads to increased cytosolic dopamine concentration and elevated production of reactive oxygen species from dopamine oxidation. Thus, the microtubule-depolymerizing activity of rotenone significantly contributes to its selective toxicity on dopaminergic neurons. Parkin, through its ability to ubiquitinate and degrade misfolded tubulin, may protect neurons from toxic accumulation of misfolded tubulin, particularly when the cells are exposed to microtubule-depolymerizing agents such as rotenone.

Selective vulnerability of dopaminergic neurons to microtubule depolymerization
J. Biol. Chem, 10.1074/jbc.M503483200

Parkinson’s disease (PD) is characterized by the specific degeneration of dopaminergic (DA) neurons in substantia nigra and has been linked to a variety of environmental and genetic factors. Rotenone, an environmental PD toxin, exhibited much greater toxicity to DA neurons in midbrain neuronal cultures than to non-DA neurons. The effect was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine or nocodazole. Microtubule depolymerization disrupted vesicular transport along microtubules and caused the accumulation of dopamine vesicles in the soma. This led to increased oxidative stress due to oxidation of cytosolic dopamine leaked from vesicles. Inhibition of dopamine metabolism significantly reduced rotenone toxicity. Thus, our results suggest that microtubule depolymerization induced by PD toxins such as rotenone plays a key role in the selective death of dopaminergic neurons.


Now, I really must go grocery shopping. I'm out of half and half and my coffee intake is in peril.