8 October 2002. Mutations in the gene for α-synuclein are known to cause early-onset, familial forms of Parkinson's disease (PD), and the protein has been found in inclusions in other neurodegenerative diseases such as Alzheimer's. Although it is thought to be involved in neuronal plasticity, the precise function of α-synuclein has remained elusive. Now, in today's PNAS early edition, researchers report that transgenic mice devoid of the protein are resistant to MPTP, a neurotoxin that induces PD like symptoms.
MPTP, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is a protoxin that crosses the blood brain barrier and is converted by enzymes such as monoamine oxidase to the active 1-methyl-4-phenylpridinium (MPP+), which poisons mitochondria and precipitates a collapse of oxidative respiration. Before it can access the organelles MPP+ must be transported across the cell membranes by specific transporters, in particular the DA transporter, which is found in the dopamine neurons of the substantia nigra, that part of the brain most damaged in Parkinson's sufferers. It is this selective delivery of MPP+ to the dopaminergic neurons that makes MPTP toxicity a useful model for PD.
William Dauer, working with principal author Rene Hen at Columbia University and collaborators at New York State Psychiatric Institute and Harvard Medical School, Boston, tested α-synuclein-null mice with the protoxin. In contrast to wildtype mice, which suffered a substantial loss of dopamine-producing cells in the substantia nigra when subjected to either chronic or acute exposure regimens, the null mice were unaffected. Dauer et al. then tried to determine what particular stage of the toxic pathway is mediated by α-synuclein. They showed that MPTP reaches the striatum in the transgenics, so access across the blood brain barrier is not prevented. They also showed that levels of the DA transporter were normal in the null mice, predicting that MPP+ should be able to penetrate their dopaminergic neurons. However, the authors showed that MPP+ has no effect on primary neuronal cultures from null mice, whereas rotenone, another mitochondrial poison, leads to cell death.
Rotenone and MPP+ are both inhibitors of mitochondrial complex I. The data suggest that the loss of α-synuclein somehow prevents MPP+ from accessing this complex. How this happens is unclear, but the fact that MPTP-induced dopamine efflux, which occurs in wildtype mice, is absent from the null mice is interesting given the intricate relationship that seems to be emerging between the neurotransmitter and the protein (see related news item and item). But as amphetamine-induced efflux of dopamine is normal in the transgenic mice, the authors predict that DA transporter function is uncompromised.
As is often the case with new findings, this paper raises more questions than it answers. It does show, though, how changes in the steady state of a single protein can profoundly increase the susceptibility to damaging environmental factors. -Tom Fagan
Reference:Dauer W, Kholodilov N, Vila M, Trillat A-C, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R. Resistance of a-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14524-9. (Abstract)