A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

Aggregation behavior in water of new imidazolium and pyrrolidinium alkycarboxylates protic ionic liquids

A novel class of anionic surfactants was prepared through the neutralization of pyrrolidine or imidazole by alkylcarboxylic acids. The compounds, namely the pyrrolidinium alkylcarboxylates ([Pyrr][CnH2n+1COO]) and imidazolium alkylcarboxylates ([Im][CnH2n+1COO]), were obtained as ionic liquids at room temperature. Their aggregation behavior has been examined as a function of the alkyl chain length (from n = 5 to 8) by surface tensiometry and conductivity. Decreases in the critical micelle concentration (cmc) were obtained, for both studied PIL families, when increasing the anionic alkyl chain length (n). Surprisingly, a large effect of the alkyl chain length was observed on the minimum surface area per surfactant molecule (Amin) and, hence the maximum surface excess concentration (Gmax) when the counterion was the pyrrolidinium cation. This unusual comportment has been interpreted in term of a balance between van der Waals and coulombic interactions. Conductimetric measurements permit determination of the degree of ionization of the micelle (a) and the molar conductivity (?M) of these surfactants as a function of n. The molar conductivities at infinite dilution in water (?8) of the [Pyrr]+ and [Im]+ cations have been then determined by using the classical Kohlraush equation. Observed change in the physicochemical, surface, and micellar properties of these new protonic ionic liquid surfactants can be linked to the nature of the cation. By comparison with classical anionic surfactants having inorganic counterions, pyrrolidinium alkylcarboxylates and imidazolium alkylcarboxylates exhibit a higher ability to aggregate in aqueous solution, demonstrating their potential applicability as surfactant.