Chapter 42 - Protein Folding and Aggregation in in vitro Models of Parkinson's Disease: Structure and Function of α-Synuclein

Abstract

This chapter explores structure and functions of α-synuclein and role of α-synuclein in Parkinson's disease (PD). The chapter also reviews protein folding and aggregation in In Vitro models of PD. α-synuclein plays an important role in idiopathic as well as familial PD. One pathway in which α-synuclein is clearly involved and which may play a crucial role in PD is the aggregation of the protein from its highly soluble native form into the amyloid fibril form that is found within Lewy body and other α-synuclein deposits. Structural studies of α-synuclein, both in its disordered-free state and in its highly helical lipid-bound state provide important insights into the protein's behavior both in vitro and in vivo. Electron microscopy using immunogold labeling shows that α-synuclein is localized to the vicinity of synaptic vesicles in presynaptic termini, but is only occasionally found directly associated with the vesicle exterior. In fractionation studies, synuclein is found predominantly in cytosolic fractions, with lesser quantities of the protein found in fractions containing synaptic vesicles. Fluorescence resonance energy transfer studies between a membrane-partitioned dye and immunofluorescently labeled α-synuclein document a close association of the protein with membranes in primary cortical neurons.