The Paradoxical Cell Biology of a-Synuclein Subhojit Roy Abstract Synucleinopathies are a group of neurodegenerative diseases charac- terized by accumulation and aggregation of the protein a-synuclein in neuronal perikarya and processes. In contrast to the proximal localization of a-synuclein in diseased states, under physiologic conditions, the bulk of a-synuclein is present in distant presynaptic terminals. Thus, pathologic conditions lead to mislocalization and aggregation of a-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, a-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 target- ing of a-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. 1 Introduction Synucleinopathies or Lewy body (LB) diseases are a heterogenous group of neuro- degenerative conditions characterized by movement disorders and/or dementias, and are second only to Alzheimer’s disease (AD) in its prevalence. Common exam- ples of these conditions include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). A key neuropathologic hallmark of these diseases is the perikaryal and neuritic accumulation and aggregation of the small, 14-kDa protein a-synu- clein into insoluble, fibrillar structures called Lewy bodies (LBs) and Lewy neurites (LN), where the wild-type (wt) protein undergoes posttranslational modifications. Results Probl Cell Differ, DOI 10.1007/400_2009_23 159 © Springer-Verlag Berlin Heidelberg 2009 S. Roy Department of Neurosciences, University of California, San Diego, 92037, CA, USA e-mail: s1roy@ucsd.edu