Two recent articles report that the expression of A53T mutant of α-synuclein causes mitochondrial dysfunction (Lee et al., 2006; Smith et al., 2005). Lee and coworkers used a transgenic mice that overexpress the human A53 mutant; as Smith and coworkers used transfected cells.
α-synuclein (alias OMIM 163890, Park1, Park4) is a rather small peptide of 140 amino acids. It can binds to phospholipase D and inhibit its activity. Some researchers think that it play a role in synaptic vesicle recycling. The mutation A53T, which occur is some forms of Parkinson's disease, apparently does not produce a significant change in the tertiary structure of the protein, and it does not cause a change in the affinity for lipid surfaces either (Bussell & Eliezer, 2004). What the mutation does, however, is to increases the propensity to form agregates (Conway et al., 1998).
Lee and co-workers found that A53T induces mitochondrial degeneration and apoptosis. Damaged mitochondria appear as swollen, shrunken or vacuolated. Interestingly, they noticed that mitochondrial DNA damage, as revealed by terminal deoxynucleotidy transferase-mediated biotinylated UTP nick end labelling (TUNEL), precedes the nuclear damage. Suggesting that mitochondria may die before the cell does.
Smith and co-workers transfected PC12 (dopaminergic) cells with a vector carrying the A53T mutant. They found that the A53T mutant decreased proteosome activity, increased the reactive oxidative species (ROS) levels, and increased the activity of caspases -3, -9, and -12, indicating activation of an apoptotic pathway.
Several mice expressing α-synuclein have shown diverse phenotype, depending on the promoter that controls the α-synuclein gene.
But here, the most curious thing is not that there are different results according to the promoter used. What is astonishing is that no damage to the
substantia nigra has been found. α-synuclein is found mutated in some forms of Parkinson's disease, whose landmark is the degeneration of dopaminergic neurones from the
substantia nigra pars compacta. A model of the disease should first reproduce this basic fact.
In any case, what we can learn from these two articles is that α-synuclein mutant may be toxic because it destroys the mitochondria.