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Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA

Special Issue: Molecular Mechanisms of Neurodegenerative Diseases

The development of Alzheimer's disease is believed to be caused by the assembly of amyloid β proteins into aggregates and the formation of extracellular senile plaques. Similar models suggest that structural misfolding and aggregation of proteins are associated with the early onset of diseases such as Parkinson's, Huntington's, and other protein deposition diseases. Initially, the aggregates were structurally characterized by traditional techniques such as x-ray crystallography, NMR, electron microscopy, and AFM. However, data regarding the structures formed during the early stages of the aggregation process were unknown. Experimental models of protein deposition diseases have demonstrated that the small oligomeric species have significant neurotoxicity. This highlights the urgent need to discover the properties of these species, to enable the development of efficient diagnostic and therapeutic strategies. The oligomers exist transiently, making it impossible to use traditional structural techniques to study their characteristics. The recent implementation of single-molecule imaging and probing techniques that are capable of probing transient states have enabled the properties of these oligomers to be characterized. Additionally, powerful computational techniques capable of structurally analyzing oligomers at the atomic level advanced our understanding of the amyloid aggregation problem. This review outlines the progress in AFM experimental studies and computational analyses with a primary focus on understanding the very first stage of the aggregation process. Experimental approaches can aid in the development of novel sensitive diagnostic and preventive strategies for protein deposition diseases, and several examples of these approaches will be discussed.
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Keywords nanomedicine; nanoimaging; atomic force microscopy; AFM; force spectroscopy;amyloids; Alzheimer's disease; Parkinson's disease; Huntington's disease

Citation: Yuri L. Lyubchenko. Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses. AIMS Molecular Science, 2015, 2(3): 190-210. doi: 10.3934/molsci.2015.3.190

References

  • 1. Dobson CM (2004) Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol 15: 3-16.    
  • 2. Fink AL (1998) Protein aggregation: folding aggregates, inclusion bodies and amyloid. Fold Des 3: R9-23.    
  • 3. Demidov VV (2004) Nanobiosensors and molecular diagnostics: a promising partnership. Expert Rev Mol Diagn 4: 267-268.    
  • 4. Ptitsyn OB (1995) How the molten globule became. Trends Biochem Sci 20: 376-379.    
  • 5. Uversky VN (2002) What does it mean to be natively unfolded? Eur J Biochem 269: 2-12.    
  • 6. Lazo ND, Grant MA, Condron MC, et al. (2005) On the nucleation of amyloid beta-protein monomer folding. Protein Sci 14: 1581-1596.
  • 7. Lyubchenko YL, Sherman S, Shlyakhtenko LS, et al. (2006) Nanoimaging for protein misfolding and related diseases. J Cell Biochem 99: 53-70.
  • 8. Knowles TP, Fitzpatrick AW, Meehan S, et al. (2007) Role of intermolecular forces in defining material properties of protein nanofibrils. Science 318: 1900-1903.    
  • 9. Tycko R (2014) Physical and structural basis for polymorphism in amyloid fibrils. Protein Sci23: 1528-1539.
  • 10. Balbach JJ, Petkova AT, Oyler NA, et al. (2002) Supramolecular structure in full-length Alzheimer's beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance. Biophys J 83: 1205-1216.    
  • 11. Petkova AT, Ishii Y, Balbach JJ, et al. (2002) A structural model for Alzheimer's beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A. 99:16742-16747.    
  • 12. Do TD, LaPointe NE, Sangwan S, et al. (2014) Factors that drive peptide assembly from native to amyloid structures: experimental and theoretical analysis of [leu-5]-enkephalin mutants. J Phys Chem B 118: 7247-7256.    
  • 13. Sawaya MR, Sambashivan S, Nelson R, et al. (2007) Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447: 453-457.    
  • 14. Baxa U, Wickner RB, Steven AC, et al. (2007) Characterization of beta-sheet structure in Ure2p1-89 yeast prion fibrils by solid-state nuclear magnetic resonance. Biochemistry 46:13149-13162.    
  • 15. Chan JC, Oyler NA, Yau WM, et al. (2005) Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p. Biochemistry 44:10669-10680.    
  • 16. Shewmaker F, Wickner RB, Tycko R (2006) Amyloid of the prion domain of Sup35p has an in-register parallel beta-sheet structure. Proc Natl Acad Sci U S A 103: 19754-19759.    
  • 17. Farrance OE, Paci E, Radford SE, et al. (2015) Extraction of accurate biomolecular parameters from single-molecule force spectroscopy experiments. ACS Nano 9: 1315-1324.    
  • 18. Wickner RB, Dyda F, Tycko R (2008) Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register beta-sheet structure. Proc Natl Acad Sci U S A 105: 2403-2408.    
  • 19. Zhang Y, Lyubchenko YL (2014) The structure of misfolded amyloidogenic dimers: computational analysis of force spectroscopy data. Biophys J 107: 2903-2910.    
  • 20. Tompa P (2009) Structural disorder in amyloid fibrils: its implication in dynamic interactions of proteins. FEBS J 276: 5406-5415.    
  • 21. Welzel AT, Maggio JE, Shankar GM, et al. (2014) Secreted amyloid beta-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Biochemistry 53: 3908-3921.    
  • 22. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathologica 126: 479-497.    
  • 23. Armstrong RA (2014) A critical analysis of the 'amyloid cascade hypothesis'. Folia Neuropathol.52: 211-225.
  • 24. Bemporad F, Chiti F (2012) Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. Chem Biol 19: 315-327.    
  • 25. Deniz AA, Mukhopadhyay S, Lemke EA (2008) Single-molecule biophysics: at the interface of biology, physics and chemistry. J R Soc Interface 5: 15-45.    
  • 26. Wang H, Duennwald ML, Roberts BE, et al. (2008) Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs. Proc Natl Acad Sci U S A 105:7159-7164.    
  • 27. Ferreon AC, Gambin Y, Lemke EA, et al. (2009) Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proc Natl Acad Sci U S A106: 5645-5650.
  • 28. Brucale M, Sandal M, Di Maio S, et al. (2009) Pathogenic mutations shift the equilibria of alpha-synuclein single molecules towards structured conformers. Chembiochem 10: 176-183.    
  • 29. Sandal M, Valle F, Tessari I, et al. (2008) Conformational equilibria in monomeric alpha-synuclein at the single-molecule level. PLoS Biol 6: e6.
  • 30. Straub JE, Thirumalai D (2010) Principles governing oligomer formation in amyloidogenic peptides. Curr Opin Struct Biol 20: 187-195.    
  • 31. Thirumalai D, Reddy G, Straub JE (2012) Role of water in protein aggregation and amyloid polymorphism. Acc Chem Res 45: 83-92.    
  • 32. Lyubchenko YL (2011) Preparation of DNA and nucleoprotein samples for AFM imaging. Micron 42: 196-206.    
  • 33. Lyubchenko YL, Krasnoslobodtsev AV, Luca S (2012) Fibrillogenesis of huntingtin and other glutamine containing proteins. In: Harris JR, editor. Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. 2012/12/12 ed: Springer Netherlands. pp. 225-251.
  • 34. Eibl RH, Moy VT (2005) Atomic force microscopy measurements of protein-ligand interactions on living cells. Methods Mol Biol 305: 439-450.
  • 35. Lee GU, Chrisey LA, Colton RJ (1994) Direct measurement of the forces between complementary strands of DNA. Science 266: 771-773.    
  • 36. Florin EL, Moy VT, Gaub HE (1994) Adhesion forces between individual ligand-receptor pairs. Science 264: 415-417.    
  • 37. McAllister C, Karymov MA, Kawano Y, et al. (2005) Protein interactions and misfolding analyzed by AFM force spectroscopy. J Mol Biol 354: 1028-1042.    
  • 38. Kransnoslobodtsev AV, Shlyakhtenko LS, Ukraintsev E, et al. (2005) Nanomedicine and Protein Misfolding Diseases. Nanomedicine 1: 300-305.    
  • 39. Yu J, Lyubchenko YL (2009) Early stages for Parkinson's development: alpha-synuclein misfolding and aggregation. J Neuroimmune Pharmacol 4: 10-16.    
  • 40. Yu J, Malkova S, Lyubchenko YL (2008) alpha-Synuclein misfolding: single molecule AFM force spectroscopy study. J Mol Biol 384: 992-1001.    
  • 41. Lyubchenko YL, Kim BH, Krasnoslobodtsev AV, et al. (2010) Nanoimaging for protein misfolding diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2: 526-543.    
  • 42. Kim BH, Palermo NY, Lovas S, et al. (2011) Single-molecule atomic force microscopy force spectroscopy study of Abeta-40 interactions. Biochemistry 50: 5154-5162.    
  • 43. Kim BH, Lyubchenko YL (2014) Nanoprobing of misfolding and interactions of amyloid beta 42 protein. Nanomedicine 10: 871-878.    
  • 44. Lv Z, Condron MM, Teplow DB, et al. (2013) Nanoprobing of the effect of Cu(2+) cations on misfolding, interaction and aggregation of amyloid beta peptide. J Neuroimmune Pharmacol 8:262-273.    
  • 45. Lv Z, Roychaudhuri R, Condron MM, et al. (2013) Mechanism of amyloid beta-protein dimerization determined using single-molecule AFM force spectroscopy. Sci Rep 3: 2880.
  • 46. Yu J, Lyubchenko YL (2009) Early stages for Parkinson's development: alpha-synuclein misfolding and aggregation. J Neuroimmune Pharmacol 4: 10-16.    
  • 47. Yu J, Malkova S, Lyubchenko YL (2008) alpha-Synuclein misfolding: single molecule AFM force spectroscopy study. J Mol Biol 384: 992-1001.    
  • 48. Lyubchenko Y, Kim B-H, Krasnoslobodtsev A, et al. (2010) Nanoimaging for protein misfolding diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2:526-543.    
  • 49. Tong Z, Mikheikin A, Krasnoslobodtsev A, et al. (2013) Novel polymer linkers for single molecule AFM force spectroscopy. Methods 60: 161-168.    
  • 50. Urbanc B, Betnel M, Cruz L, et al. (2010) Elucidation of amyloid beta-protein oligomerization mechanisms: discrete molecular dynamics study. J Am Chem Soc 132: 4266-4280.    
  • 51. Gu L, Liu C, Guo Z (2013) Structural insights into Abeta42 oligomers using site-directed spin labeling. J Biol Chem 288: 18673-18683.    
  • 52. Ball KA, Phillips AH, Wemmer DE, et al. (2013) Differences in beta-strand Populations of Monomeric Abeta40 and Abeta42. Biophys J 104: 2714-2724.    
  • 53. Maji SK, Ogorzalek Loo RR, Inayathullah M, et al. (2009) Amino acid position-specific contributions to amyloid beta-protein oligomerization. J Biol Chem 284: 23580-23591.    
  • 54. Krasnoslobodtsev AV, Volkov IL, Asiago JM, et al. (2013) alpha-Synuclein Misfolding Assessed with Single Molecule AFM Force Spectroscopy: Effect of Pathogenic Mutations. Biochemistry52: 7377-7386.
  • 55. Heise H, Celej MS, Becker S, et al. (2008) Solid-state NMR reveals structural differences between fibrils of wild-type and disease-related A53T mutant alpha-synuclein. J Mol Biol 380:444-450.    
  • 56. Comellas G, Lemkau LR, Nieuwkoop AJ, et al. (2011) Structured Regions of α-Synuclein Fibrils Include the Early-Onset Parkinson's Disease Mutation Sites. J Mol Biol 411: 881-895.    
  • 57. Haupt C, Leppert J, Ronicke R, et al. (2012) Structural basis of beta-amyloid-dependent synaptic dysfunctions. Angew Chem Int Ed Engl 51: 1576-1579.    
  • 58. Yu J, Warnke J, Lyubchenko YL (2011) Nanoprobing of alpha-synuclein misfolding and aggregation with atomic force microscopy. Nanomedicine 7: 146-152.    
  • 59. Krasnoslobodtsev AV, Peng J, Asiago JM, et al. (2012) Effect of spermidine on misfolding and interactions of alpha-synuclein. PloS One 7: e38099.    
  • 60. Bertoncini CW, Fernandez CO, Griesinger C, et al. (2005) Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation. J Biol Chem 280: 30649-30652.    
  • 61. Brucale M, Sandal M, Di Maio S, et al. (2009) Pathogenic mutations shift the equilibria of alpha-synuclein single molecules towards structured conformers. Chembiochem 10: 176-183.    
  • 62. Losasso V, Pietropaolo A, Zannoni C, et al. (2011) Structural role of compensatory amino acid replacements in the alpha-synuclein protein. Biochemistry 50: 6994-7001.    
  • 63. Roede JR, Uppal K, Park Y, et al. (2013) Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study. PloS One 8: e77629.
  • 64. Evans E (2001) Probing the relation between force--lifetime--and chemistry in single molecular bonds. Annu Rev Biophys Biomol Struct 30: 105-128.    
  • 65. Lv Z, Krasnoslobodtsev AV, Zhang Y, et al. (2015) Direct Detection of alpha-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis. Biophys J 108: 2038-2047.    
  • 66. Kim BH, Lyubchenko YL (2013) Nanoprobing of misfolding and interactions of amyloid beta 42 protein. Nanomedicine 10: 871-878.
  • 67. Lovas S, Zhang Y, Yu J, et al. (2013) Molecular mechanism of misfolding and aggregation of Abeta(13-23). J Phys Chem B 117: 6175-6186.    
  • 68. Portillo AM, Krasnoslobodtsev AV, Lyubchenko YL (2012) Effect of electrostatics on aggregation of prion protein Sup35 peptide. J Phys Condens Matter 24: 164205.    
  • 69. Lovas S, Zhang Y, Lyubchenko YL (2012) Insight into Aß misfolding and aggregation. In: Kokotos G, Copnstantinou-Kokotou, V and Matsoukas, J., editor. Peptides 2012. Proceedings of the 32nd European Peptide Symposium ed. Athens, Greece: European Peptide Society, University of Athens, Laboratory of Organic Chemistry. pp. 56-57.
  • 70. Tjernberg LO, Tjernberg A, Bark N, et al. (2002) Assembling amyloid fibrils from designed structures containing a significant amyloid beta-peptide fragment. Biochem J 366: 343-351.
  • 71. Balbach JJ, Ishii Y, Antzutkin ON, et al. (2000) Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39: 13748-13759.    
  • 72. Booth DR, Sunde M, Bellotti V, et al. (1997) Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385: 787-793.    
  • 73. Uversky VN (2015) Proteins without unique 3D structures: biotechnological applications of intrinsically unstable/disordered proteins. Biotechnol J 10: 356-366.    
  • 74. Castillo V, Ventura S (2009) Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases. PLoS Comput Biol 5: e1000476.    
  • 75. Lakowicz JR (2006) Principles of Fluorescence Spectroscopy. Singapore: Springer. 954 p.
  • 76. Piana S, Klepeis JL, Shaw DE (2014) Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations. Curr Opin Struct Biol 24: 98-105.    
  • 77. Basak S, Chattopadhyay K (2014) Studies of protein folding and dynamics using single molecule fluorescence spectroscopy. Phys Chem Chem Phys 16: 11139-11149.    
  • 78. Gedeon PC, Thomas JR, Madura JD (2015) Accelerated molecular dynamics and protein conformational change: a theoretical and practical guide using a membrane embedded model neurotransmitter transporter. Methods Mol Biol 1215: 253-287.    
  • 79. Ono K, Condron MM, Teplow DB (2009) Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci U S A 106: 14745-14750.    
  • 80. Shankar GM, Li S, Mehta TH, et al. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14: 837-842.    
  • 81. Shankar GM, Bloodgood BL, Townsend M, et al. (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27: 2866-2875.    
  • 82. Yankner BA, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3: 41-66.    
  • 83. He X, Giurleo JT, Talaga DS (2009) Role of small oligomers on the amyloidogenic aggregation free-energy landscape. J Mol Biol 395: 134-154.

 

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