Folding and misfolding of alpha-synuclein on membranes

Abstract

The protein alpha-synuclein is considered to play a major role in the etiology of Parkinson’s disease. Because it is found in a classic amyloid fibril form within the characteristic intra-neuronal Lewy body deposits of the disease, aggregation of the protein is thought to be of critical importance, but the context in which the protein undergoes aggregation within cells remains unknown. The normal function of synucleins is poorly understood, but appears to involve membrane interactions, and in particular reversible binding to synaptic vesicle membranes. Structural studies of different states of alpha-synuclein, in the absence and presence of membranes or membrane mimetics, have led to models of how membrane-bound forms of the protein may contribute both to functional properties of the protein, as well as to membrane-induced self-assembly and aggregation. This article reviews this area, with a focus on a particular model that has emerged in the past few years.

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

“…The role of α-Syn inclusion bodies in the pathogenesis of neurodegenerative diseases is not completely understood; however, α-Syn interacts with phospholipids on plasma membranes and may be involved in altered phospholipid metabolism (41). Aberrant phospholipid metabolism has also been suggested as an important process in diabetic embryopathy (15).…”

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

“…[10] The sequence of α-synuclein can be divided into three domains: (i) a positively charged N-terminal region that contains a series of conserved motifs, proposed to enable membrane-induced amphipathic α-helix formation, (ii) a hydrophobic central region which is essential for β-structure formation, and (iii) a negatively charged C-terminus that remains unstructured in both the aggregated and membrane-bound state. [2,8] Depending on membrane physico-chemical properties, several distinct binding modes have been suggested for α-synuclein. [11] Nevertheless, the N-terminal ~1 00 residues (encompassing N-terminus and central region) undergo coil-helix transition upon α membrane binding.…”

“…[9,12,13,15] The membrane affinity of α-synuclein is highly influenced by bilayer curvature, charge and phase state, chemical composition of the solution (buffer), and lipid:protein ratio. [7][8][9] α-Synuclein may interact better with highly curved surfaces of small unilamellar vesicles (SUVs), [16][17][18] which resemble the size of synaptic vesicles. [19] Depending on the lipid model system the α-helix adopts extended or horseshoe-like conformation.…”

“…[5] Although membrane-binding properties of α-synuclein have been extensively studied, there is a lack of consensus regarding α-synuclein membrane preferences and its effect on the bilayer structure. [8,9] In aqueous solution and in intracellular environment, α-synuclein exists mainly as a disordered and highly dynamic 140-residue monomer. [10] The sequence of α-synuclein can be divided into three domains: (i) a positively charged N-terminal region that contains a series of conserved motifs, proposed to enable membrane-induced amphipathic α-helix formation, (ii) a hydrophobic central region which is essential for β-structure formation, and (iii) a negatively charged C-terminus that remains unstructured in both the aggregated and membrane-bound state.…”

Chameleon behaviour of a-synuclein : brownian dynamics simulations of protein aggregation

“…Whenever numerical values are required we will refer to α-synuclein, a small 14 kDa intrinsically disordered protein, composed of 140 aminoacids (AA), found mainly in neuronal tissue and commonly associated with Parkinson's disease. Also known as the 'protein chameleon', α-synuclein adopts a disordered state in a solvent, curls up into an alpha-helix against a membrane [45,218] or vesicle [52], and folds into cross β sheets in fibrils or amyloids [118,212]. In this chapter, we will focus on the disordered and the β-rich conformations.…”