Neural degeneration and the transport of neurotransmitters

A number of neurodegenerative diseases selectively affect distinct neuronal populations, but the mechanisms responsible for selective cell vulnerability have generally remained unclear. The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces the selective degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson's disease. The plasma membrane dopamine transporter mediates this selective toxicity through accumulation of the active metabolite N-methyl-4-phenylpyridinium (MPP+). In contrast, the vesicular amine transporter protects against this form of injury by sequestering the toxin from its primary site of action in mitochondria. Together with the identification of defects in glutamate transport from patients with amyotrophic lateral sclerosis, these observations suggest that neurotransmitter transport may have a major role in neurodegenerative disease. The recent cloning of cDNAs encoding these transport proteins will help to explore this hypothesis.