J Biol Chem,
How genetic and environmental factors interact in Parkinson''s disease is poorly understood. We have now compared the patterns of vulnerability and rescue of C. elegans with genetic modifications of three different genetic factors implicated in PD. We observed that expressing alpha-synuclein, deleting parkin (K08E3.7) or knocking down DJ-1 (B0432.2) or parkin, produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than non-transgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (FeII or CuII) or etoposide compared to non-transgenic nematodes. Each of the PD-related lines was also partially rescued by the anti-oxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate (DbetaHB) or the anti-apoptotic bile acid tauroursodeoxycholic acid (TUDCA). Complete protection in all lines was achieved by combining DbetaHB with TUDCA but not with probucol. These results show that diverse PD-related genetic modifications disrupt mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.