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<0.0005) the number of cells stained positive for Bcl-2, while significantly (P<0.05) decreasing the percentage of cells stained positive for BAX. These short
peptides could serve as lead compounds for the design of
peptidomimetic drugs to treat PD and related disorders.