Systematic in Vivo Analysis of the Intrinsic Determinants of Amyloid Beta Pathogenicity

Overview

Journal PLoS Biol

Specialty Biology

Date 2007 Nov 2

PMID 17973577

Citations 94

Authors

Leila M Luheshi

Gian Gaetano Tartaglia

Ann-Christin Brorsson

Amol P Pawar

Ian E Watson

Fabrizio Chiti

Michele Vendruscolo

David A Lomas

Christopher M Dobson

Damian C Crowther

Affiliations

Soon will be listed here.

Abstract

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Abeta42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Abeta42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Abeta and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism.

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References

Townsend M, Shankar G, Mehta T, Walsh D, Selkoe D . Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol. 2006; 572(Pt 2):477-92. PMC: 1779683. DOI: 10.1113/jphysiol.2005.103754. View

Barnhart M, Chapman M . Curli biogenesis and function. Annu Rev Microbiol. 2006; 60:131-47. PMC: 2838481. DOI: 10.1146/annurev.micro.60.080805.142106. View

Bukau B, Weissman J, Horwich A . Molecular chaperones and protein quality control. Cell. 2006; 125(3):443-51. DOI: 10.1016/j.cell.2006.04.014. View

Buchanan R, Benzer S . Defective glia in the Drosophila brain degeneration mutant drop-dead. Neuron. 1993; 10(5):839-50. DOI: 10.1016/0896-6273(93)90200-b. View

Chiti F, Taddei N, Baroni F, Capanni C, Stefani M, Ramponi G . Kinetic partitioning of protein folding and aggregation. Nat Struct Biol. 2002; 9(2):137-43. DOI: 10.1038/nsb752. View

Cleary J, Walsh D, Hofmeister J, Shankar G, Kuskowski M, Selkoe D . Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2004; 8(1):79-84. DOI: 10.1038/nn1372. View

Gidalevitz T, Ben-Zvi A, Ho K, Brignull H, Morimoto R . Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science. 2006; 311(5766):1471-4. DOI: 10.1126/science.1124514. View

Cohen E, Bieschke J, Perciavalle R, Kelly J, Dillin A . Opposing activities protect against age-onset proteotoxicity. Science. 2006; 313(5793):1604-10. DOI: 10.1126/science.1124646. View

Dobson C . An accidental breach of a protein's natural defenses. Nat Struct Mol Biol. 2006; 13(4):295-7. DOI: 10.1038/nsmb0406-295. View

10.

IDA N, Hartmann T, Pantel J, Schroder J, Zerfass R, Forstl H . Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem. 1996; 271(37):22908-14. DOI: 10.1074/jbc.271.37.22908. View

11.

Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2005; 38(1):24-6. DOI: 10.1038/ng1718. View

12.

Chiti F, Dobson C . Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006; 75:333-66. DOI: 10.1146/annurev.biochem.75.101304.123901. View

13.

Crowther D, Kinghorn K, Miranda E, Page R, Curry J, Duthie F . Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease. Neuroscience. 2005; 132(1):123-35. DOI: 10.1016/j.neuroscience.2004.12.025. View

14.

Chiti F, Stefani M, Taddei N, Ramponi G, Dobson C . Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature. 2003; 424(6950):805-8. DOI: 10.1038/nature01891. View

15.

Selkoe D . Folding proteins in fatal ways. Nature. 2003; 426(6968):900-4. DOI: 10.1038/nature02264. View

16.

Bilen J, Bonini N . Drosophila as a model for human neurodegenerative disease. Annu Rev Genet. 2005; 39:153-71. DOI: 10.1146/annurev.genet.39.110304.095804. View

17.

Westerman M, Mariash A, Kotilinek L, Kawarabayashi T, Younkin L, Carlson G . The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002; 22(5):1858-67. PMC: 6758862. View

18.

Pawar A, Dubay K, Zurdo J, Chiti F, Vendruscolo M, Dobson C . Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases. J Mol Biol. 2005; 350(2):379-92. DOI: 10.1016/j.jmb.2005.04.016. View

19.

Finelli A, Kelkar A, Song H, Yang H, Konsolaki M . A model for studying Alzheimer's Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci. 2004; 26(3):365-75. DOI: 10.1016/j.mcn.2004.03.001. View

20.

Fandrich M, Dobson C . The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J. 2002; 21(21):5682-90. PMC: 131070. DOI: 10.1093/emboj/cdf573. View