Transgenic ALS mice show increased vulnerability to the mitochondrial toxins MPTP and 3-nitropropionic acid

The pathogenesis of neurodegenerative diseases may involve a genetic predis position acting in concert with environmental toxins. To test this hypothes is we examined whether transgenic mice with the G93A mutation in Cu,Zn supe roxide dismutase show increased vulnerability to either 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3-NP), Compared to littermate controls G93A transgenic mice showed a greater loss of striat al dopamine, DOPAC, and HVA at 50, 70, and 120 days of age following admini stration of MPTP; however, cell loss in the substantia nigra was not greate r. The G93A transgenic mice showed significantly increased vulnerability to striatal lesions produced by 3-NP compared with littermate controls at 120 days of age. The finding that G93A mice show increased vulnerability to mi tochondrial toxins further implicates mitochondrial dysfunction in the path ogenesis of neuronal death in these mice. The findings support the hypothes is that a genetic defect can increase susceptibility to environmental toxin s and that this may play a role in the pathogenesis of neurodegenerative di seases. (C) 2001 Academic Press.