The inhibitory effects of biomimetically designed peptides on α-synuclein aggregation.

Parkinson's disease is characterized by accumulation of inclusion bodies in dopaminergic neurons, where insoluble and fibrillar α-synuclein makes up the major component of these inclusion bodies. So far, several strategies have been applied in order to suppress α-synuclein aggregation and toxicity in Parkinson's disease. In the present study, a new database has been established by segmentation of all the proteins deposited in protein Data Bank. The database data base was searched for the sequences which adopt β structure and are identical or very similar to the regions of α-synuclein which are involved in aggregation. The adjacent β strands of the found sequences were chosen as the peptide inhibitors of α-synuclein aggregation. Two of the predicted peptides, namely KISVRV and GQTYVLPG, were experimentally proved to be efficient in suppressing aggregation of α-synuclein in vitro. Moreover, KISVRV exhibited the ability to disrupt oligomers of α-syn which are assumed to be the pathogenic species in Parkinson's disease.

[1]  E. Masliah,et al.  Non-A beta component of Alzheimer's disease amyloid (NAC) is amyloidogenic. , 1995, Biochemistry.

[2]  G. Hadjigeorgiou,et al.  Mutated α-synuclein gene in two Greek kindreds with familial PD: Incomplete penetrance? , 1999, Neurology.

[3]  Mark A. Schmitz,et al.  Semirational design of Jun-Fos coiled coils with increased affinity: Universal implications for leucine zipper prediction and design. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Harrison,et al.  Discordant and chameleon sequences: Their distribution and implications for amyloidogenicity , 2011, Protein science : a publication of the Protein Society.

[5]  Vladimir N. Uversky,et al.  Amino acid determinants of α‐synuclein aggregation: putting together pieces of the puzzle , 2002 .

[6]  W. Nicklas,et al.  IV. MPTP, MPP+ and mitochondrial function , 1987 .

[7]  Nigel J Fullwood,et al.  A strategy for designing inhibitors of α ‐synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  Michel Goedert,et al.  Alpha-synuclein and neurodegenerative diseases , 2001, Nature Reviews Neuroscience.

[9]  Taro Saito,et al.  Demonstration of a role for α-synuclein as a functional microtubule-associated protein , 2004 .

[10]  G. Irvine,et al.  Identification of the region of non‐Aβ component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity , 2001, Journal of neurochemistry.

[11]  Mark R Cookson,et al.  The biochemistry of Parkinson's disease. , 2005, Annual review of biochemistry.

[12]  D. Eliezer,et al.  Alpha-Synuclein Function and Dysfunction on Cellular Membranes , 2014, Experimental neurobiology.

[13]  S. Kang,et al.  beta-Sheet-breaking peptides inhibit the fibrillation of human alpha-synuclein. , 2009, Biochemical and biophysical research communications.

[14]  S. Kang,et al.  The hexapeptide PGVTAV suppresses neurotoxicity of human α-synuclein aggregates. , 2011, Biochemical and biophysical research communications.

[15]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[16]  X. Roucou,et al.  Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization , 2013, Molecular Neurodegeneration.

[17]  E. Masliah,et al.  The role of α-synuclein assembly and metabolism in the pathogenesis of Lewy body disease , 2007, Journal of Molecular Neuroscience.

[18]  Z. Wszolek,et al.  Reduced expression of the G209A α‐synuclein allele in familial parkinsonism , 1999 .

[19]  A. Doig,et al.  Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR. , 2008, Journal of the American Chemical Society.

[20]  Michel Goedert,et al.  Mutation E46K increases phospholipid binding and assembly into filaments of human α‐synuclein , 2004 .

[21]  Makoto Hashimoto,et al.  Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease , 1998, Brain Research.

[22]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[23]  Olaf Riess,et al.  AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease , 1998, Nature Genetics.

[24]  Igor B Kuznetsov,et al.  Comparative computational analysis of prion proteins reveals two fragments with unusual structural properties and a pattern of increase in hydrophobicity associated with disease‐promoting mutations , 2004, Protein science : a publication of the Protein Society.

[25]  Regina M Murphy,et al.  Peptide aggregation in neurodegenerative disease. , 2002, Annual review of biomedical engineering.

[26]  Hongmao Sun,et al.  Opportunities and challenges of developing peptide drugs in the pharmaceutical industry. , 2009, Advances in experimental medicine and biology.

[27]  M. Polymeropoulos,et al.  Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding alpha-synuclein. , 1999, American journal of human genetics.

[28]  J Q Trojanowski,et al.  A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly* , 2001, The Journal of Biological Chemistry.

[29]  V. Lee,et al.  Are Ubiquitination Pathways Central to Parkinson's Disease? , 2003, Cell.

[30]  Henning Stahlberg,et al.  The fold of α-synuclein fibrils , 2008, Proceedings of the National Academy of Sciences.

[31]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[32]  D. Eliezer,et al.  Conformational properties of alpha-synuclein in its free and lipid-associated states. , 2001, Journal of molecular biology.

[33]  S. Snyder,et al.  Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Gazit,et al.  Inhibiting α-Synuclein Oligomerization by Stable Cell-Penetrating β-Synuclein Fragments Recovers Phenotype of Parkinson's Disease Model Flies , 2010, PloS one.

[35]  Armin Giese,et al.  Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding , 2007, The Journal of Neuroscience.

[36]  Hyun-Jung Koo,et al.  Aggregation-defective alpha-synuclein mutants inhibit the fibrillation of Parkinson's disease-linked alpha-synuclein variants. , 2009, Biochemical and biophysical research communications.

[37]  M. Nikkhah,et al.  Disruption of mitochondrial membrane integrity induced by amyloid aggregates arising from variants of SOD1. , 2013, International journal of biological macromolecules.

[38]  Glenda M. Halliday,et al.  Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr α‐synuclein mutation , 2001 .

[39]  Paul H. Axelsen,et al.  The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation* , 2005, Journal of Biological Chemistry.

[40]  M. Feany,et al.  Aggregated α-Synuclein Mediates Dopaminergic Neurotoxicity In Vivo , 2007, The Journal of Neuroscience.

[41]  C. Griesinger,et al.  Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[43]  P. Lansbury,et al.  Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Scott R. Presnell,et al.  Origins of structural diversity within sequentially identical hexapeptides , 1993, Protein science : a publication of the Protein Society.

[45]  V. Torchilin.  Intracellular delivery of protein and peptide therapeutics. , 2008, Drug discovery today. Technologies.

[46]  Koichi Abe,et al.  Peptide ligand screening of α-synuclein aggregation modulators by in silico panning , 2007, BMC Bioinformatics.

[47]  J. Massano,et al.  Clinical approach to Parkinson's disease: features, diagnosis, and principles of management. , 2012, Cold Spring Harbor perspectives in medicine.

[48]  Diego Guidolin,et al.  α‐Synuclein and Parkinson's disease , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  T. Golde,et al.  Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α‐synuclein , 2014, Journal of neurochemistry.

[50]  R. Petersen,et al.  Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases. , 2013, Biochimica et biophysica acta.

[51]  J. Trojanowski,et al.  Mechanisms of Parkinson's Disease Linked to Pathological α-Synuclein: New Targets for Drug Discovery , 2006, Neuron.

[52]  Saikat Ghosh,et al.  The Parkinson's disease-associated H50Q mutation accelerates α-Synuclein aggregation in vitro. , 2013, Biochemistry.

[53]  Natsuki Kobayashi,et al.  Pyrroloquinoline quinone (PQQ) prevents fibril formation of α-synuclein , 2006 .

[54]  L. Bubacco,et al.  Structural insights on physiological functions and pathological effects of ±‐synuclein , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  S. Michnick,et al.  Oligomerization domain-directed reassembly of active dihydrofolate reductase from rationally designed fragments. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[57]  David R. Brown,et al.  Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein , 2015, Biomolecules.

[58]  V. Buchman,et al.  Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease , 2003, Neuropharmacology.

[59]  A. Doig,et al.  Studies of the aggregation of an amyloidogenic α-synuclein peptide fragment , 2005 .

[60]  L. Serpell,et al.  Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R. Riek,et al.  Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation , 2015, Scientific Reports.

[62]  D. Neill,et al.  Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filaments , 1998, FEBS letters.

[63]  H. Jäckle,et al.  Pre‐fibrillar α‐synuclein variants with impaired β‐structure increase neurotoxicity in Parkinson's disease models , 2009, The EMBO journal.

[64]  S. Becker,et al.  Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Harish Cheruvara,et al.  Intracellular Screening of a Peptide Library to Derive a Potent Peptide Inhibitor of α-Synuclein Aggregation* , 2015, The Journal of Biological Chemistry.

[66]  H. Zoghbi,et al.  α-synuclein—a link between Parkinson and Alzheimer diseases? , 1997, Nature Genetics.

[67]  D. Eliezer,et al.  Residual Structure and Dynamics in Parkinson's Disease-associated Mutants of α-Synuclein* , 2001, The Journal of Biological Chemistry.

[68]  Olga Pletnikova,et al.  Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  P. Y. Chou,et al.  Conformational parameters for amino acids in helical, beta-sheet, and random coil regions calculated from proteins. , 1974, Biochemistry.

[70]  R. Jakes,et al.  Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of α‐synuclein protein implicated in Parkinson's disease , 1998, FEBS letters.

[71]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[72]  E. Masliah,et al.  α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress , 2000 .