Novel therapeutic strategies for the treatment of protein-misfolding diseases

Jean-Christophe Rochet

doi:10.1017/S1462399407000385

Novel therapeutic strategies for the treatment of protein-misfolding diseases

Published online by Cambridge University Press: 28 June 2007

Jean-Christophe Rochet

Show author details

Jean-Christophe Rochet: Affiliation:
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 410A, West Lafayette, IN 47907, USA. Tel: +1 765 494 1413; Fax: +1 765 494 1414; E-mail: [email protected]

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 9 , Issue 17 , June 2007 , pp. 1 - 34

DOI: https://doi.org/10.1017/S1462399407000385 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

1Dobson, C.M. (2003) Protein folding and misfolding. Nature 426, 884-890CrossRef Google Scholar PubMed

2Dahlgren, K.N. et al. (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277, 32046-32053CrossRef Google Scholar PubMed

3Walsh, D.M. et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539CrossRef Google Scholar PubMed

4Lesne, S. et al. (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352-357CrossRef Google Scholar PubMed

5Cohen, E. et al. (2006) Opposing activities protect against age-onset proteotoxicity. Science 313, 1604-1610CrossRef Google Scholar PubMed

6Arrasate, M. et al. (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805-810CrossRef Google Scholar PubMed

7Silveira, J.R. et al. (2005) The most infectious prion protein particles. Nature 437, 257-261CrossRef Google Scholar PubMed

8Reixach, N. et al. (2004) Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci U S A 101, 2817-2822CrossRef Google Scholar PubMed

9Volles, M.J. et al. (2001) Vesicle permeabilization by protofibrillar α-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry 40, 7812-7819CrossRef Google Scholar PubMed

10Lashuel, H.A. et al. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291CrossRef Google Scholar PubMed

11Kayed, R. et al. (2004) Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279, 46363-46366CrossRef Google Scholar PubMed

12Hashimoto, M. et al. (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromolecular Med 4, 21-36CrossRef Google Scholar PubMed

13Mattson, M.P. and Sherman, M. (2003) Perturbed signal transduction in neurodegenerative disorders involving aberrant protein aggregation. Neuromolecular Med 4, 109-132CrossRef Google Scholar PubMed

14Rego, A.C. and de Almeida, L.P. (2005) Molecular targets and therapeutic strategies in Huntington's disease. Curr Drug Targets CNS Neurol Disord 4, 361-381CrossRef Google Scholar PubMed

15Nelson, R. and Eisenberg, D. (2006) Recent atomic models of amyloid fibril structure. Curr Opin Struct Biol 16, 260-265CrossRef Google Scholar PubMed

16Rochet, J.C. and Lansbury, P.T. Jr. (2000) Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10, 60-68CrossRef Google Scholar PubMed

17Petkova, A.T., Yau, W.M. and Tycko, R. (2006) Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils. Biochemistry 45, 498-512CrossRef Google Scholar PubMed

18Petkova, A.T. et al. (2005) Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 307, 262-265CrossRef Google Scholar PubMed

19Torok, M. et al. (2002) Structural and dynamic features of Alzheimer's Abeta peptide in amyloid fibrils studied by site-directed spin labeling. J Biol Chem 277, 40810-40815CrossRef Google Scholar PubMed

20Williams, A.D. et al. (2004) Mapping abeta amyloid fibril secondary structure using scanning proline mutagenesis. J Mol Biol 335, 833-842CrossRef Google Scholar PubMed

21Whittemore, N.A. et al. (2005) Hydrogen-deuterium (H/D) exchange mapping of Abeta 1-40 amyloid fibril secondary structure using nuclear magnetic resonance spectroscopy. Biochemistry 44, 4434-4441CrossRef Google Scholar PubMed

22Kheterpal, I. et al. (2006) Structural differences in Abeta amyloid protofibrils and fibrils mapped by hydrogen exchange–mass spectrometry with on-line proteolytic fragmentation. J Mol Biol 361, 785-795CrossRef Google Scholar PubMed

23Shivaprasad, S. and Wetzel, R. (2006) Scanning cysteine mutagenesis analysis of Abeta-(1–40) amyloid fibrils. J Biol Chem 281, 993-1000CrossRef Google Scholar PubMed

24Luhrs, T. et al. (2005) 3D structure of Alzheimer's amyloid-beta(1-42) fibrils. Proc Natl Acad Sci U S A 102, 17342-17347CrossRef Google Scholar PubMed

25Der-Sarkissian, A. et al. (2003) Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling. J Biol Chem 278, 37530-37535CrossRef Google Scholar PubMed

26Del Mar, C. et al. (2005) Structure and properties of alpha-synuclein and other amyloids determined at the amino acid level. Proc Natl Acad Sci U S A 102, 15477-15482CrossRef Google Scholar PubMed

27Heise, H. et al. (2005) Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci U S A 102, 15871-15876CrossRef Google Scholar PubMed

28Makin, O.S. et al. (2005) Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci U S A 102, 315-320CrossRef Google Scholar

29Sambashivan, S. et al. (2005) Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure. Nature 437, 266-269CrossRef Google Scholar PubMed

30Sciarretta, K.L. et al. (2006) Spatial separation of beta-sheet domains of beta-amyloid: disruption of each beta-sheet by N-methyl amino acids. Biochemistry 45, 9485-9495CrossRef Google Scholar PubMed

31Yan, L.M. et al. (2006) Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis. Proc Natl Acad Sci U S A 103, 2046-2051CrossRef Google Scholar PubMed

32Sciarretta, K.L., Gordon, D.J. and Meredith, S.C. (2006) Peptide-based inhibitors of amyloid assembly. Methods Enzymol 413, 273-312CrossRef Google Scholar PubMed

33Sato, T. et al. (2006) Inhibitors of amyloid toxicity based on beta-sheet packing of Abeta40 and Abeta42. Biochemistry 45, 5503-5516CrossRef Google Scholar PubMed

34Conway, K.A. et al. (2001) Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct. Science 294, 1346-1349CrossRef Google Scholar PubMed

35Rochet, J.C. et al. (2004) Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease. J Mol Neurosci 23, 23-34CrossRef Google Scholar PubMed

36Blanchard, B.J. et al. (2004) Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A 101, 14326-14332CrossRef Google Scholar PubMed

37Kim, W. et al. (2006) A high-throughput screen for compounds that inhibit aggregation of the Alzheimer's peptide. ACS Chem Biol 1, 461-469CrossRef Google Scholar PubMed

38Chirita, C., Necula, M. and Kuret, J. (2004) Ligand-dependent inhibition and reversal of tau filament formation. Biochemistry 43, 2879-2887CrossRef Google Scholar PubMed

39Heiser, V. et al. (2002) Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Natl Acad Sci U S A 99 Suppl 4, 16400-16406CrossRef Google Scholar PubMed

40Hockly, E. et al. (2006) Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease. Neurobiol Dis 21, 228-236CrossRef Google Scholar PubMed

41Wang, J. et al. (2005) Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci 6, 1CrossRef Google Scholar PubMed

42Zhang, X. et al. (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A 102, 892-897CrossRef Google Scholar PubMed

43Desai, U.A. et al. (2006) Biologically active molecules that reduce polyglutamine aggregation and toxicity. Hum Mol Genet 15, 2114-2124CrossRef Google Scholar PubMed

44Bodner, R.A. et al. (2006) Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A 103, 4246-4251CrossRef Google Scholar PubMed

45Bertsch, U. et al. (2005) Systematic identification of antiprion drugs by high-throughput screening based on scanning for intensely fluorescent targets. J Virol 79, 7785-7791CrossRef Google Scholar PubMed

46Kocisko, D.A. et al. (2003) New inhibitors of scrapie-associated prion protein formation in a library of 2000 drugs and natural products. J Virol 77, 10288-10294CrossRef Google Scholar

47Kocisko, D.A. and Caughey, B. (2006) Mefloquine, an antimalaria drug with antiprion activity in vitro, lacks activity in vivo. J Virol 80, 1044-1046CrossRef Google Scholar PubMed

48Colon, W. and Kelly, J.W. (1992) Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-8660CrossRef Google Scholar PubMed

49Johnson, S.M. et al. (2005) Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc Chem Res 38, 911-921CrossRef Google Scholar PubMed

50Fry, D.C. (2006) Protein-protein interactions as targets for small molecule drug discovery. Biopolymers 84, 535-552Google Scholar PubMed

51Adamski-Werner, S.L. et al. (2004) Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem 47, 355-374CrossRef Google Scholar PubMed

52Hammarstrom, P. et al. (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713-716CrossRef Google Scholar PubMed

53Morais-de-Sa, E. et al. (2004) The crystal structure of transthyretin in complex with diethylstilbestrol: a promising template for the design of amyloid inhibitors. J Biol Chem 279, 53483-53490CrossRef Google Scholar PubMed

54Johnson, S.M. et al. (2005) Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. J Med Chem 48, 1576-1587CrossRef Google Scholar PubMed

55Petrassi, H.M. et al. (2005) Potent and selective structure-based dibenzofuran inhibitors of transthyretin amyloidogenesis: kinetic stabilization of the native state. J Am Chem Soc 127, 6662-6671CrossRef Google Scholar PubMed

56Wiseman, R.L., Green, N.S. and Kelly, J.W. (2005) Kinetic stabilization of an oligomeric protein under physiological conditions demonstrated by a lack of subunit exchange: implications for transthyretin amyloidosis. Biochemistry 44, 9265-9274CrossRef Google Scholar PubMed

57Green, N.S., Foss, T.R. and Kelly, J.W. (2005) Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis. Proc Natl Acad Sci U S A 102, 14545-14550CrossRef Google Scholar PubMed

58Hough, M.A. et al. (2004) Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. Proc Natl Acad Sci U S A 101, 5976-5981CrossRef Google Scholar PubMed

59Ray, S.S. et al. (2005) Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation. Proc Natl Acad Sci U S A 102, 3639-3644CrossRef Google Scholar PubMed

60Loo, T.W. and Clarke, D.M. (2007) Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev Mol Med 9, 1-18CrossRef Google Scholar PubMed

61De Jonghe, C. et al. (2001) Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet 10, 1665-1671CrossRef Google Scholar PubMed

62Wolfe, M.S. (2002) APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's disease. Int Immunopharmacol 2, 1919-1929CrossRef Google Scholar PubMed

63Hamaguchi, T., Ono, K. and Yamada, M. (2006) Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer's disease. Cell Mol Life Sci 63, 1538-1552CrossRef Google Scholar PubMed

64Weggen, S. et al. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212-216CrossRef Google Scholar PubMed

65Beher, D. et al. (2004) Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. J Biol Chem 279, 43419-43426CrossRef Google Scholar

66Zhou, Y. et al. (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302, 1215-1217CrossRef Google Scholar PubMed

67Desire, L. et al. (2005) RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases Abeta production in vitro and in vivo. J Biol Chem 280, 37516-37525CrossRef Google Scholar PubMed

68Manes, S. et al. (2003) From rafts to crafts: membrane asymmetry in moving cells. Trends Immunol 24, 320-326CrossRef Google Scholar PubMed

69Phiel, C.J. et al. (2003) GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423, 435-439CrossRef Google Scholar PubMed

70Netzer, W.J. et al. (2003) Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 100, 12444-12449CrossRef Google Scholar

71Fraering, P.C. et al. (2005) gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem 280, 41987-41996Google Scholar PubMed

72Best, J.D. et al. (2007) The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse. J Pharmacol Exp Ther 320, 552-558CrossRef Google Scholar

73Hong, L. et al. (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290, 150-153CrossRef Google Scholar PubMed

74Cole, D.C. et al. (2006) Acylguanidines as small-molecule beta-secretase inhibitors. J Med Chem 49, 6158-6161CrossRef Google Scholar PubMed

75Freskos, J.N. et al. (2007) Design of potent inhibitors of human beta-secretase. Part 2. Bioorg Med Chem Lett 17, 78-81CrossRef Google Scholar PubMed

76Ghosh, A.K. et al. (2006) Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors. J Am Chem Soc 128, 5310-5311CrossRef Google Scholar PubMed

77Hanessian, S. et al. (2005) Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics. J Med Chem 48, 5175-5190Google Scholar PubMed

78Stachel, S.J. et al. (2006) Macrocyclic inhibitors of beta-secretase: functional activity in an animal model. J Med Chem 49, 6147-6150CrossRef Google Scholar PubMed

79Chang, W.P. et al. (2004) In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors. J Neurochem 89, 1409-1416Google Scholar PubMed

80Laird, F.M. et al. (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25, 11693-11709CrossRef Google Scholar

81Hu, X. et al. (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9, 1520-1525CrossRef Google Scholar PubMed

82Willem, M. et al. (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664-666CrossRef Google Scholar PubMed

83Saura, C.A. et al. (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25, 6755-6764CrossRef Google Scholar PubMed

84Sastre, M. et al. (2006) Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A 103, 443-448CrossRef Google Scholar PubMed

85Espeseth, A.S. et al. (2005) Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics. J Biol Chem 280, 17792-17797CrossRef Google Scholar PubMed

86Leissring, M.A. et al. (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087-1093CrossRef Google Scholar PubMed

87Choi, D.S. et al. (2006) PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc Natl Acad Sci U S A 103, 8215-8220CrossRef Google Scholar PubMed

88Saito, T. et al. (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11, 434-439CrossRef Google Scholar PubMed

89Gafni, J. et al. (2004) Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J Biol Chem 279, 20211-20220CrossRef Google Scholar PubMed

90Graham, R.K. et al. (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179-1191CrossRef Google Scholar PubMed

91Berke, S.J. et al. (2004) Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem 89, 908-918Google Scholar PubMed

92Haacke, A. et al. (2006) Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet 15, 555-568Google Scholar PubMed

93Cattaneo, E., Zuccato, C. and Tartari, M. (2005) Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci 6, 919-930CrossRef Google Scholar PubMed

94Li, W. et al. (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc Natl Acad Sci U S A 102, 2162-2167CrossRef Google Scholar PubMed

95Liu, C.W. et al. (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280, 22670-22678CrossRef Google Scholar PubMed

96Gamblin, T.C. et al. (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A 100, 10032-10037CrossRef Google Scholar PubMed

97Yin, H. and Kuret, J. (2006) C-terminal truncation modulates both nucleation and extension phases of tau fibrillization. FEBS Lett 580, 211-215CrossRef Google Scholar PubMed

98Page, L.J. et al. (2005) Metalloendoprotease cleavage triggers gelsolin amyloidogenesis. Embo J 24, 4124-4132CrossRef Google Scholar PubMed

99Chen, F. et al. (2004) Posttranslational modifications of tau–role in human tauopathies and modeling in transgenic animals. Curr Drug Targets 5, 503-515CrossRef Google Scholar PubMed

100Alonso, A. et al. (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98, 6923-6928CrossRef Google Scholar PubMed

101Duff, K. and Planel, E. (2005) Untangling memory deficits. Nat Med 11, 826-827CrossRef Google Scholar PubMed

102Wittmann, C.W. et al. (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711-714CrossRef Google Scholar PubMed

103Andorfer, C. et al. (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25, 5446-5454Google Scholar PubMed

104Santacruz, K. et al. (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476-481CrossRef Google Scholar

105Le Corre, S. et al. (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci U S A 103, 9673-9678CrossRef Google Scholar PubMed

106Alonso Adel, C. et al. (2006) Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc Natl Acad Sci U S A 103, 8864-8869CrossRef Google Scholar PubMed

107Shulman, J.M. and Feany, M.B. (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165, 1233-1242CrossRef Google Scholar PubMed

108Avila, J. (2006) Tau phosphorylation and aggregation in Alzheimer's disease pathology. FEBS Lett 580, 2922-2927CrossRef Google Scholar PubMed

109Lucas, J.J. et al. (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. Embo J 20, 27-39CrossRef Google Scholar PubMed

110Jackson, G.R. et al. (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509-519CrossRef Google Scholar PubMed

111Cruz, J.C. et al. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471-483CrossRef Google Scholar PubMed

112Noble, W. et al. (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555-565CrossRef Google Scholar PubMed

113Liu, S.J. et al. (2004) Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem 279, 50078-50088CrossRef Google Scholar PubMed

114Sato, S. et al. (2006) Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J Neurochem 98, 1573-1584CrossRef Google Scholar PubMed

115Hoshi, M. et al. (2003) Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci U S A 100, 6370-6375CrossRef Google Scholar PubMed

116Takashima, A. (2006) GSK-3 is essential in the pathogenesis of Alzheimer's disease. J Alzheimers Dis 9, 309-317CrossRef Google Scholar PubMed

117Noble, W. et al. (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 102, 6990-6995CrossRef Google Scholar PubMed

118Bhat, R. et al. (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem 278, 45937-45945CrossRef Google Scholar PubMed

119Patrick, G.N. et al. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615-622CrossRef Google Scholar PubMed

120Zheng, Y.L. et al. (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. Embo J 24, 209-220CrossRef Google Scholar PubMed

121Plattner, F., Angelo, M. and Giese, K.P. (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem 281, 25457-25465CrossRef Google Scholar PubMed

122Fujiwara, H. et al. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4, 160-164CrossRef Google Scholar PubMed

123Anderson, J.P. et al. (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281, 29739-29752CrossRef Google Scholar PubMed

124Smith, W.W. et al. (2005) alpha-Synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25, 5544-5552CrossRef Google Scholar PubMed

125Chen, L. and Feany, M.B. (2005) alpha-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8, 657-663CrossRef Google Scholar

126Kim, E.J. et al. (2006) Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 281, 33250-33257CrossRef Google Scholar PubMed

127Tabner, B.J. et al. (2005) Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem 280, 35789-35792CrossRef Google Scholar PubMed

128Barnham, K.J. et al. (2003) Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem 278, 42959-42965CrossRef Google Scholar PubMed

129Butterfield, D.A. and Boyd-Kimball, D. (2005) The critical role of methionine 35 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity. Biochim Biophys Acta 1703, 149-156CrossRef Google Scholar PubMed

130Hou, L. et al. (2002) Methionine 35 oxidation reduces fibril assembly of the amyloid abeta-(1–42) peptide of Alzheimer's disease. J Biol Chem 277, 40173-40176CrossRef Google Scholar PubMed

131Palmblad, M., Westlind-Danielsson, A. and Bergquist, J. (2002) Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers. J Biol Chem 277, 19506-19510CrossRef Google Scholar PubMed

132Bitan, G. et al. (2003) A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization. J Am Chem Soc 125, 15359-15365CrossRef Google Scholar PubMed

133Zhang, Q. et al. (2004) Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc Natl Acad Sci U S A 101, 4752-4757CrossRef Google Scholar PubMed

134Ono, K. et al. (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. J Neurochem 87, 172-181CrossRef Google Scholar PubMed

135Masuda, M. et al. (2006) Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 45, 6085-6094CrossRef Google Scholar PubMed

136Yang, F. et al. (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280, 5892-5901CrossRef Google Scholar PubMed

137Matsubara, E. et al. (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease. J Neurochem 85, 1101-1108CrossRef Google Scholar

138Feng, Z. et al. (2006) Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease. Free Radic Biol Med 40, 101-109CrossRef Google Scholar

139Abdul, H.M. et al. (2006) Acetyl-l-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. J Neurosci Res 84, 398-408CrossRef Google Scholar PubMed

140Ritchie, C.W. et al. (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60, 1685-1691CrossRef Google Scholar PubMed

141Norris, E.H. et al. (2003) Effects of oxidative and nitrative challenges on α-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278, 27230-27240CrossRef Google Scholar PubMed

142Yamin, G., Uversky, V.N. and Fink, A.L. (2003) Nitration inhibits fibrillation of human α-synuclein in vitro by formation of soluble oligomers. FEBS Lett 542, 147-152CrossRef Google Scholar PubMed

143Cole, N.B. et al. (2005) Metal-catalyzed oxidation of alpha synuclein: helping to define the relationship between oligomers, protofilaments and filaments. J Biol Chem 280, 9678-9690CrossRef Google Scholar

144Glaser, C.B. et al. (2005) Methionine oxidation, alpha-synuclein and Parkinson's disease. Biochim Biophys Acta 1703, 157-169CrossRef Google Scholar PubMed

145Mirzaei, H. et al. (2006) Identification of rotenone-induced modifications in alpha-synuclein using affinity pull-down and tandem mass spectrometry. Anal Chem 78, 2422-2431CrossRef Google Scholar PubMed

146Bosco, D.A. et al. (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2, 249-253CrossRef Google Scholar PubMed

147Zhu, M. et al. (2004) The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem 279, 26846-26857CrossRef Google Scholar PubMed

148Ono, K. and Yamada, M. (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97, 105-115CrossRef Google Scholar PubMed

149Giorgini, F. et al. (2005) A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 37, 526-531CrossRef Google Scholar PubMed

150Wyttenbach, A. et al. (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 11, 1137-1151CrossRef Google Scholar PubMed

151Firdaus, W.J. et al. (2006) Analysis of oxidative events induced by expanded polyglutamine huntingtin exon 1 that are differentially restored by expression of heat shock proteins or treatment with an antioxidant. Febs J 273, 3076-3093CrossRef Google Scholar PubMed

152Firdaus, W.J. et al. (2006) Huntingtin inclusion bodies are iron-dependent centers of oxidative events. Febs J 273, 5428-5441CrossRef Google Scholar PubMed

153Dias-Santagata, D. et al. (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117, 236-245CrossRef Google Scholar PubMed

154Deng, H.X. et al. (2006) Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci U S A 103, 7142-7147CrossRef Google Scholar

155Muchowski, P.J. and Wacker, J.L. (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6, 11-22CrossRef Google Scholar PubMed

156Cuervo, A.M. et al. (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295CrossRef Google Scholar PubMed

157Evans, C.G., Wisen, S. and Gestwicki, J.E. (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 281, 33182-33191CrossRef Google Scholar PubMed

158Wilhelmus, M.M. et al. (2006) Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res 1089, 67-78CrossRef Google Scholar PubMed

159Klucken, J. et al. (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279, 25497-25502CrossRef Google Scholar PubMed

160Zhou, Y. et al. (2004) Analysis of alpha-synuclein-associated proteins by quantitative proteomics. J Biol Chem 279, 39155-39164CrossRef Google Scholar PubMed

161Auluck, P.K. et al. (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865-868CrossRef Google Scholar

162Dedmon, M.M. et al. (2005) Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 280, 14733-14740CrossRef Google Scholar PubMed

163Huang, C. et al. (2006) Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. J Mol Biol 364, 323-336CrossRef Google Scholar PubMed

164Zourlidou, A., Payne Smith, M.D. and Latchman, D.S. (2004) HSP27 but not HSP70 has a potent protective effect against alpha-synuclein-induced cell death in mammalian neuronal cells. J Neurochem 88, 1439-1448CrossRef Google Scholar PubMed

165Outeiro, T.F. et al. (2006) Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. Biochem Biophys Res Commun 351, 631-638CrossRef Google Scholar PubMed

166Wacker, J.L. et al. (2004) Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 11, 1215-1222CrossRef Google Scholar PubMed

167Miller, V.M. et al. (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci 25, 9152-9161CrossRef Google Scholar PubMed

168Jana, N.R. et al. (2005) Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 280, 11635-11640CrossRef Google Scholar PubMed

169Al-Ramahi, I. et al. (2006) CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem 281, 26714-26724CrossRef Google Scholar PubMed

170Behrends, C. et al. (2006) Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 23, 887-897CrossRef Google Scholar PubMed

171Kitamura, A. et al. (2006) Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nat Cell Biol 8, 1163-1170CrossRef Google Scholar PubMed

172Tam, S. et al. (2006) The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nat Cell Biol 8, 1155-1162CrossRef Google Scholar PubMed

173Gestwicki, J.E., Crabtree, G.R. and Graef, I.A. (2004) Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation. Science 306, 865-869Google Scholar PubMed

174Drysdale, M.J. et al. (2006) Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel 9, 483-495Google Scholar PubMed

175McCollum, A.K. et al. (2006) Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 66, 10967-10975CrossRef Google Scholar PubMed

176McLean, P.J. et al. (2004) Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321, 665-669CrossRef Google Scholar PubMed

177Auluck, P.K., Meulener, M.C. and Bonini, N.M. (2005) Mechanisms of suppression of {alpha}-synuclein neurotoxicity by geldanamycin in Drosophila. J Biol Chem 280, 2873-2878CrossRef Google Scholar PubMed

178Hay, D.G. et al. (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13, 1389-1405CrossRef Google Scholar

179Shen, H.Y. et al. (2005) Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J Biol Chem 280, 39962-39969CrossRef Google Scholar PubMed

180Ansar, S. et al. (2007) A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity. Bioorg Med Chem Lett 17, 1984-1990CrossRef Google Scholar PubMed

181Westerheide, S.D. et al. (2004) Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279, 56053-56060CrossRef Google Scholar PubMed

182Johnston, J.A., Ward, C.L. and Kopito, R.R. (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143, 1883-1898CrossRef Google Scholar PubMed

183Iwata, A. et al. (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280, 40282-40292CrossRef Google Scholar PubMed

184Ravikumar, B. et al. (2005) Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 37, 771-776CrossRef Google Scholar PubMed

185Lee, H.J. and Lee, S.J. (2002) Characterization of cytoplasmic alpha-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells. J Biol Chem 277, 48976-48983CrossRef Google Scholar

186Lee, H.J. et al. (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24, 1888-1896CrossRef Google Scholar PubMed

187Webb, J.L. et al. (2003) alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278, 25009-25013CrossRef Google Scholar PubMed

188Tanaka, M. et al. (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279, 4625-4631CrossRef Google Scholar PubMed

189Waelter, S. et al. (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12, 1393-1407CrossRef Google Scholar PubMed

190Taylor, J.P. et al. (2003) Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 12, 749-757CrossRef Google Scholar PubMed

191Iwata, A. et al. (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci U S A 102, 13135-13140CrossRef Google Scholar PubMed

192Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11, 1107-1117CrossRef Google Scholar PubMed

193Rubinsztein, D.C. (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780-786CrossRef Google Scholar PubMed

194Ravikumar, B. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36, 585-595CrossRef Google Scholar PubMed

195Berger, Z. et al. (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15, 433-442CrossRef Google Scholar PubMed

196Vignot, S. et al. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16, 525-537CrossRef Google Scholar PubMed

197Sarkar, S. et al. (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170, 1101-1111CrossRef Google Scholar PubMed

198Sarkar, S. et al. (2007) Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and {alpha}-synuclein. J Biol Chem 282, 5641-5652CrossRef Google Scholar PubMed

199Miller, V.M. et al. (2004) Targeting Alzheimer's disease genes with RNA interference: an efficient strategy for silencing mutant alleles. Nucleic Acids Res 32, 661-668CrossRef Google Scholar PubMed

200Saito, Y. et al. (2005) Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model. J Biol Chem 280, 42826-42830CrossRef Google Scholar PubMed

201Sapru, M.K. et al. (2006) Silencing of human alpha-synuclein in vitro and in rat brain using lentiviral-mediated RNAi. Exp Neurol 198, 382-390CrossRef Google Scholar PubMed

202Cooper, A.A. et al. (2006) alpha-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313, 324-328CrossRef Google Scholar PubMed

203Poon, H.F. et al. (2005) Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice–a model of familial amyotrophic lateral sclerosis. Free Radic Biol Med 39, 453-462CrossRef Google Scholar PubMed

204Nollen, E.A. et al. (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A 101, 6403-6408CrossRef Google Scholar PubMed

205Morfini, G. et al. (2006) JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 9, 907-916CrossRef Google Scholar PubMed

206Kelly, J.W. (1996) Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol 6, 11-17CrossRef Google Scholar PubMed

207Zoghbi, H.Y. and Orr, H.T. (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23, 217-247CrossRef Google Scholar PubMed

208Taylor, J.P., Hardy, J. and Fischbeck, K.H. (2002) Toxic proteins in neurodegenerative disease. Science 296, 1991-1995CrossRef Google Scholar PubMed

209Caughey, B. and Lansbury, P.T. (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26, 267-298CrossRef Google Scholar PubMed

210Ross, C.A. and Poirier, M.A. (2004) Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl, S10-17CrossRef Google Scholar PubMed

211Chaudhuri, T.K. and Paul, S. (2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. Febs J 273, 1331-1349CrossRef Google Scholar PubMed

212Tycko, R. (2006) Molecular structure of amyloid fibrils: insights from solid-state NMR. Q Rev Biophys 39, 1-55CrossRef Google Scholar PubMed

Article contents

Novel therapeutic strategies for the treatment of protein-misfolding diseases

Abstract

Access options

Article purchase

Temporarily unavailable

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

Novel therapeutic strategies for the treatment of protein-misfolding diseases

Abstract

Access options

Article purchase

Temporarily unavailable

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests