The paradoxical cell biology of alpha-Synucle.

Synucleinopathies are a group of neurodegenerative diseases characterized by accumulation and aggregation of the protein alpha-synuclein in neuronal perikarya and processes. In contrast to the proximal localization of alpha-synuclein in diseased states, under physiologic conditions, the bulk of alpha-synuclein is present in distant presynaptic terminals. Thus, pathologic conditions lead to mislocalization and aggregation of alpha-synuclein in neuronal cell bodies, and an outstanding question relates to the cell-biological mechanisms that can lead to such mislocalization. Like most other synaptic proteins, alpha-synuclein is synthesized in the neuronal perikarya and then transported into axons and synaptic domains. Accordingly, it has been hypothesized that disturbances in biogenesis/axonal transport or presynaptic targeting of alpha-synuclein can lead to its mislocalization in diseased states. In this chapter, key observations that lead to this hypothesis are presented in addition to a review of some recent literature that has directly addressed this issue. Finally, conflicting results that have resulted from such studies are also highlighted, and a view is offered to reconcile these controversies.