1. Function of a-synuclein:

a-synuclein (Snca) is a pre-synaptic and nuclear protein, the normal function of which is unknown.  What role its normal function might play in PD is unknown, but sequestration of the protein in Lewy body inclusions may prevent it from carrying out its normal function. It is found only in vertebrates, so is clearly not necessary for basic synaptic function.  Mice lacking the protein have some subtle synaptic phenotypes, but are healthy overall and live a normal lifespan.  Thus Snca's function may be more important under stress conditions, or it may be functionally redundant with other proteins.  To better understand the normal role of the protein, we are using microarray analysis to compare mice deleted for Snca and WT controls.  Another approach will be an ENU sensitization screen to identify proteins of redundant function, interacting partners, and pathways in which Snca operates.  Once the normal function of Snca is better defined, its role in PD can be assessed. a-synuclein was originally identified as being both pre-synaptic and nuclear, but subsequent work has focused on its synaptic function.  We have analysed the expression of Snca throughout brain, and have found that in the substantia nigra, it is found in the nuclei of dopaminergic nigral neurons.  This nuclear localization can be seen in several other regions such as in CA3 pyramidal hippocampal neurons, and a few regions of the cerebral cortex.  This localization may be lost at advanced age.  While Snca lacks a nuclear localization signal, it is smaller than the nuclear pore exclusion limit.  Passive diffusion is not the mechanism for nuclear localization however, as in some neurons Snca is predominantly cytoplasmic, and in others, it is concentrated in nuclei.  A current project involves investigating the mechanism by which Snca is localized to nuclei.  Understanding this mechanism may provide some insight into Snca's nuclear function.