The function of ␣-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, ␣-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that ␣-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type ␣-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant ␣-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant ␣-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo-and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the ␣-synuclein gene, electroporation of wild-type ␣-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P ␣-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, ␣-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.

The cytosolic protein alpha-synuclein is enriched at the pre-synaptic terminals of almost all types of neurons in the central nervous system. alpha-Synuclein overexpression and the expression of three different mutants have been shown to sustain the pathogenesis of selected forms of Parkinson's disease. The localization of the protein and the defects found in knocked out or transgenic animals suggest a role of alpha-synuclein in the regulation of synaptic efficiency. However, the precise function of the protein and the molecular mechanisms of its action are still unclear. At synapses the synaptic vesicle release cycle is a finely tuned process composed of sequential steps that require the interconnected participation of several proteins and cytoskeletal elements. Actin microfilaments are required for the regulation of synaptic vesicle mobilization between different functional pools, for their organization at the active zone and influence the exocytotic process. We recently identified actin as a possible target of alpha-synuclein function. Through its binding to actin and the regulation of actin dynamics, alpha-synuclein could participate in the tuning of the vesicle release process, thereby modulating synaptic function and plasticity.

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Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non-Hodgkin's lymphoma (NHL).It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV-associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)-chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy.In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines.