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<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.
El-Agnaf
Omar M A
OM
Department of Biological Sciences, Lancaster University, Lancaster, UK. o.el-agnaf@lancaster.ac.uk
Paleologou
Katerina E
KE
Greer
Brett
B
Abogrein
Abdulmawala M
AM
King
Jenny E
JE
Salem
Sultan A
SA
Fullwood
Nigel J
NJ
Benson
Fiona E
FE
Hewitt
Rebecca
R
Ford
Kirstie J
KJ
Martin
Francis L
FL
Harriott
Patrick
P
Cookson
Mark R
MR
Allsop
David
D
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis; D016229:Amyloid beta-Peptides / Q000032:analysis; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007501:Iron / Q000633:toxicity; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019151:Peptide Library; D010455:Peptides; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D051843:Synucleins; D051844:alpha-Synuclein; D051028:bcl-2-Associated X Protein
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000978:Antiparkinson Agents; C494826:BAX protein, human; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D019151:Peptide Library; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C078592:amyloid beta-protein (1-40); D051028:bcl-2-Associated X Protein; C015462:polyarginine; D007501:Iron