Alpha-synuclein is a small protein that normally sits at nerve endings and helps synaptic vesicles release their messenger. In Parkinson's it folds the wrong way, sticks together and ends up in Lewy bodies. Press play to follow one nerve ending, then change the genes to see what more protein, or weaker clearance, does.
SNCA copiesClearance
Schematic, not to scale.
From one molecule to a Lewy body
Strain injected in rats
Schematic. In people this takes years and happens in three dimensions.
Does it start in the gut?
One idea is that synuclein pathology can begin in the nerves of the gut and climb the vagus nerve to the brainstem. If so, cutting the vagus, or removing the appendix, might lower the risk. Large registry studies have tested this, with mixed results. Filled dots are results whose 95% confidence interval excludes no effect.
Synuclein is not the only thread. Toxins that poison mitochondria, recessive genes for mitochondrial quality control, and iron all point at the same vulnerable neurons. The genes are in Genes and inheritance and the trials that target these steps in Toward a cure.