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

ABSTRACT Convergent biochemical and genetic evidence suggests that the formation of α‐synuclein (α‐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 α‐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 α‐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 α‐syn sequence, and identified amino acid residues 64‒100 of α‐syn as the binding region responsible for its self‐ association. Modified short peptides containing α‐syn amino acid sequences from part of this binding region (residues 69‒72), named α‐syn inhibitors (ASI), were found to interact with full‐ length α‐syn and block its assembly into both early oligomers and mature amyloid‐like fibrils. We also developed a cell‐permeable inhibitor of α‐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 α‐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