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102 Etiology and Pathophysiology of Parkinson's Disease

Contradictory to these current models of membrane-bound α-synuclein that have been deduced mostly from NMR studies, limited proteolysis experiments have indicated that the C-terminal part of membrane-bound α-synuclein has a more rigid structure. The negatively charged C-terminus appears to bind Ca2+ in the presence of SDS micelles, and in doing so it becomes sufficiently rigid and structured to resist extensive proteolysis (de Laureto et al., 2006). In another study based on site-directed fluorescence labeling, they also examined the effects of Ca2+ on the acidic tail conformation of lipid-bound α-synuclein (Tamamizu-Kato et al., 2006). Here, they suggested that the Ca2+ either bridges α-synuclein to the membrane, possibly by coordinating with the negative charge on the α-synuclein acidic tail and the acidic head-groups in the phospholipid bilayer, or it facilitates the traversing of the

Another study highlighted the role of the physical parameters of the membrane mimetic in determining the α-synuclein conformation (Trexler & Rhoades, 2009). Single molecule Förster resonance energy transfer was used to probe the helical structure of α-synuclein bound to SDS micelles and LUVs. Single and double Cys α-synuclein mutants were engineered to allow for site-specific labeling with maleimide fluorophores. When bound to highly curved detergent micelles, α-synuclein formed a bent-helix, whereas the structure of the elongated helix was adopted when bound to the more physiological 100-nm-diameter

Single-molecule Förster resonance energy transfer was also used to provide evidence for the structural interplay between the broken and extended α-helix structures of α-synuclein, as induced by the binding of α-synuclein to SDS and phospholipid SUVs (Ferreon et al., 2009). The switch between a broken and an extended helical structure can be triggered by changing the concentrations of the binding partners or by varying the curvature of the binding surfaces presented by the micelles or bilayers composed of SDS. The use of lipid vesicles of various compositions showed that a low fraction of the negatively charged lipids, as similar to that found in biological membranes, was sufficient to drive α-synuclein binding and folding that resulted in the induction of the extended helical structure (Ferreon et al.,

The structure of the N-terminal domain of α-synuclein has also been determined using theoretical methods (Mihajlovic & Lazaridis, 2008). This computional study of the binding of truncated α-synuclein (residues 1-95) to planar bilayers showed that α-synuclein forms a bent helix, with the largest bend around residue 47. This bending of the helix was not due to the protein sequence or membrane-protein interactions, but to the collective motions of the

In this chapter, we have presented the state-of-the-art for the field of α-synuclein structure, and for its fibril formation and interactions with membranes. There are still many unanswered questions regarding the correlation between α-synuclein membrane affinity, and its function and its role in synucleinopathies. As the disruption of membranes by αsynuclein correlates with the binding affinity of α-synuclein for particular membrane compositions and with the induced helical conformation of α-synuclein, this suggests that inappropriate membrane permeabilization is the cause of cell dysfunction, and even cell

membrane bilayer by this segment of α-synuclein (Tamamizu-Kato et al., 2006).

**7.4 Analysis of α-synuclein structure with other methods** 

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**6** 

*Italy* 

**Alpha-Synuclein, Oxidative Stress and** 

**in Dopaminergic Neurodegeneration** 

Giovanni Stefanoni1,2, Gessica Sala1, Lucio Tremolizzo1,2,

Laura Brighina1,2 and Carlo Ferrarese1,2

*2Department of Neurology, San Gerardo Hospital, Monza.* 

**Autophagy Failure: Dangerous Liaisons** 

*1Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca*

The molecular mechanisms of neurodegeneration in Parkinson's disease and the cause of the selective dopaminergic neuronal loss are mostly unknown. Many pathogenetic factors have been found to play a role but the relationships among these factors, together with the reasons of the high vulnerability of dopaminergic neurons to them, have not been completely defined. Only a small fraction of Parkinson's disease cases have a defined etiology: this fraction include the monogenic hereditary variants of the disease and the sporadic cases determined by prolonged exposition to toxic agents inhibiting mitochondrial complex I, such as 1,1'-dimethyl-4,4'-5 bipyridinium (paraquat), rotenone and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinson's disease-related toxins and pathogenetic mutations have been indispensable to create cell and animal models with the aim to clarify the molecular physiopathology of the disease. Little is known about the primitive causes of idiopathic Parkinson's disease, that probably represents a multi-factorial disease influenced by various genetic and environmental factors, all characterized by high incidence in general population. The different risk factors together would contribute to initiate the complex pathogenetic sequence of events leading to the death of dopaminergic

Recently, Parkinson's disease has been placed in the large category of neurodegenerative diseases caused by protein misfolding. In particular, alpha-synuclein has been proposed as the central and most specific factor implied in the pathogenesis of this syndrome, which, as a consequence, has been classified among synucleinopathies, together with dementia with Lewy bodies and multiple system atrophy, other neurodegenerative diseases having alpha-

Aim of this chapter is to provide an organic revision of evidences for the involvement of alpha-synuclein in the pathogenesis of Parkinson's disease. We will define the mechanisms responsible for the toxic gain of function of α-synuclein and the processes triggered by aberrant alpha-synuclein and mediating its neurotoxic effect. Particular attention will be paid to establish the links that correlate the deleterious action of alpha-synuclein with oxidative stress and with the efficiency of the processes involved in the clearance of aberrant

**1. Introduction** 

neurons.

synuclein pathology as a major feature.

*Molecular Basis of Disease*, Vol.1782, No.10, (October 2008), pp. 581-585, ISSN 0925- 4439

