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Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders

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Abstract

Misfolded and aggregated proteins build up in neurodegenerative illnesses, which causes neuronal dysfunction and ultimately neuronal death. In the last few years, there has been a significant upsurge in the level of interest towards the function of molecular chaperones in the control of misfolding and aggregation. The crucial molecular chaperones implicated in neurodegenerative illnesses are covered in this review article, along with a variety of their different methods of action. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones serve critical roles in preserving protein homeostasis. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones have integral roles in preserving regulation of protein balance. It has been demonstrated that aging, a significant risk factor for neurological disorders, affects how molecular chaperones function. The aggregation of misfolded proteins and the development of neurodegeneration may be facilitated by the aging-related reduction in chaperone activity. Molecular chaperones have also been linked to the pathophysiology of several instances of neuron withering illnesses, enumerating as Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. Molecular chaperones have become potential therapy targets concerning with the prevention and therapeutic approach for brain disorders due to their crucial function in protein homeostasis and their connection to neurodegenerative illnesses. Protein homeostasis can be restored, and illness progression can be slowed down by methods that increase chaperone function or modify their expression. This review emphasizes the importance of molecular chaperones in the context of neuron withering disorders and their potential as therapeutic targets for brain disorders.

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References

  1. Labbadia J, Morimoto RI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–68

    Article  CAS  PubMed  Google Scholar 

  3. Dobson CM (2002) Protein-misfolding diseases: Getting out of shape. Nature 418(6899):729–730

    Article  CAS  PubMed  Google Scholar 

  4. Trippier PC, Jansen Labby K, Hawker DD, Mataka JJ, Silverman RB (2013) Target-and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers. J Med Chem 56(8):3121–3147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stefani M, Dobson CM (2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med 81:678–699

    Article  CAS  PubMed  Google Scholar 

  6. Halliday M, Mallucci GR (2014) Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 76:169–174

    Article  CAS  PubMed  Google Scholar 

  7. Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11(4):301–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kampinga HH, Bergink S (2016) Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurology 15(7):748–759

    Article  CAS  PubMed  Google Scholar 

  9. Sajjad MU, Samson B, Wyttenbach A (2010) Heat shock proteins: therapeutic drug targets for chronic neurodegeneration? Curr Pharm Biotechnol 11(2):198–215

    Article  CAS  PubMed  Google Scholar 

  10. Ellis RJ, Hemmingsen SM (1989) Molecular chaperones: proteins essential for the biogenesis of some macromolecular structures. Trends Biochem Sci 14(8):339–342

    Article  CAS  PubMed  Google Scholar 

  11. Laskey RA, Honda BM, Mills AD, Finch JT (1978) Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275(5679):416–420

    Article  CAS  PubMed  Google Scholar 

  12. Pelham HRB (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46(7):959–961

    Article  CAS  PubMed  Google Scholar 

  13. Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A et al (2014) A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep 9(3):1135–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Picard D (2002) Heat-shock protein 90, a chaperone for folding and regulation. Cellul Mol Life Sci CMLS 59:1640–1648

    Article  CAS  Google Scholar 

  15. Aligue R, Akhavan-Niak H, Russell P (1994) A role for Hsp90 in cell cycle control: Wee1 tyrosine kinase activity requires interaction with Hsp90. EMBO J 13(24):6099–6106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Young JC, Moarefi I, Hartl FU (2001) Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154(2):267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hutchison KA, Dittmar KD, Pratt WB (1994) All of the factors required for assembly of the glucocorticoid receptor into a functional heterocomplex with heat shock protein 90 are preassociated in a self-sufficient protein folding structure, a “foldosome”. J Biol Chem 269(45):27894–27899

    Article  CAS  PubMed  Google Scholar 

  18. Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, Hartl FU, Moarefi I (2000) Structure of TPR domain–peptide complexes: critical elements in the assembly of the Hsp70–Hsp90 multichaperone machine. Cell 101(2):199–210

    Article  CAS  PubMed  Google Scholar 

  19. Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM et al (2000) The ATPase cycle of Hsp90 drives a molecular ‘clamp’via transient dimerization of the N-terminal domains. EMBO J 19(16):4383–4392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Obermann WMJ, Sondermann H, Russo AA, Pavletich NP, Hartl FU (1998) In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J Cell Biol 143(4):901–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Freeman BC, Morimoto RI (1996) The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. EMBO J 15(12):2969–2979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pratt WB (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc Soc Exp Biol Med 217(4):420–434

    Article  CAS  PubMed  Google Scholar 

  23. Kihm AJ, Kong YI, Hong W, Russell JE, Rouda S, Adachi K, Simon MC, Blobel GA et al (2002) An abundant erythroid protein that stabilizes free α-haemoglobin. Nature 417(6890):758–763

    Article  CAS  PubMed  Google Scholar 

  24. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295(5561):1852–1858

    Article  CAS  PubMed  Google Scholar 

  25. Dougan DA, Mogk A, Zeth K, Turgay K, Bukau B (2002) AAA+ proteins and substrate recognition, it all depends on their partner in crime. FEBS Lett 529(1):6–10

    Article  CAS  PubMed  Google Scholar 

  26. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2(8):476–483

    Article  CAS  PubMed  Google Scholar 

  27. Pilon M, Schekman R (1999) Protein translocation: how Hsp70 pulls it off. Cell 97(6):679–682

    Article  CAS  PubMed  Google Scholar 

  28. Flaherty KM, McKay DB, Kabsch W, Holmes KC (1991) Similarity of the three-dimensional structures of actin and the ATPase fragment of a 70-kDa heat shock cognate protein. Proc Natl Acad Sci 88(11):5041–5045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu X, Zhao X, Burkholder WF, Gragerov A, Ogata CM, Gottesman ME, Hendrickson WA (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272(5268):1606–1614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rüdiger S, Germeroth L, Schneider-Mergener J, Bukau B (1997) Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J 16(7):1501–1507

    Article  PubMed  PubMed Central  Google Scholar 

  31. Szabo A, Langer T, Schröder H, Flanagan J, Bukau B, Hartl FU (1994) The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE. Proc Natl Acad Sci 91(22):10345–10349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Langer T, Lu C, Echols H, Flanagan J, Hayer MK, Hartl FU (1992) Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature 356(6371):683–689

    Article  CAS  PubMed  Google Scholar 

  33. Höhfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16(20):6209–6216

    Article  PubMed  PubMed Central  Google Scholar 

  34. Young JC, Hoogenraad NJ, Hartl FU (2003) Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112(1):41–50

    Article  CAS  PubMed  Google Scholar 

  35. Takayama S, Reed JC (2001) Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol 3(10):E237–E241

    Article  CAS  PubMed  Google Scholar 

  36. Lüders J, Demand J, Höhfeld JR (2000) The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem 275(7):4613–4617

    Article  PubMed  Google Scholar 

  37. Alberti S, Demand J, Esser C, Emmerich N, Schild H, Hohfeld J (2002) Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem 277(48):45920–45927

    Article  CAS  PubMed  Google Scholar 

  38. Wiederkehr T, Bukau B, Buchberger A (2002) Protein turnover: a CHIP programmed for proteolysis. Curr Biol 12(1):R26–R28

    Article  CAS  PubMed  Google Scholar 

  39. Ciechanover A, Kwon YT (2017) Protein quality control by molecular chaperones in neurodegeneration. Front Neurosci 11:185

    Article  PubMed  PubMed Central  Google Scholar 

  40. Itoh H, Komatsuda A, Ohtani H, Wakui H, Imai H, Sawada KI, Otaka M, Ogura M et al (2002) Mammalian HSP60 is quickly sorted into the mitochondria under conditions of dehydration. Eur J Biochem 269(23):5931–5938

    Article  CAS  PubMed  Google Scholar 

  41. Ranford JC, Coates ARM, Henderson B (2000) Chaperonins are cell-signalling proteins: the unfolding biology of molecular chaperones. Expert Rev Mol Med 2(8):1–17

    Article  CAS  PubMed  Google Scholar 

  42. Tutar L, Tutar Y (2010) Heat shock proteins; an overview. Curr Pharm Biotechnol 11(2):216–222

    Article  CAS  PubMed  Google Scholar 

  43. Cheng MY, Hartl FU, Norwich AL (1990) The mitochondrial chaperonin hsp60 is required for its own assembly. Nature 348(6300):455–458

    Article  CAS  PubMed  Google Scholar 

  44. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci 95(11):6469–6473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Haslbeck M (2002) sHsps and their role in the chaperone network. Cellul Mol Life Sci CMLS 59:1649–1657

    Article  CAS  Google Scholar 

  46. Zhu Z, Reiser G (2018) The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases. Neurochem Int 115:69–79

    Article  PubMed  Google Scholar 

  47. Jakob U, Buchner J (1994) Assisting spontaneity: the role of Hsp90 and small Hsps as molecular chaperones. Trends Biochem Sci 19(5):205–211

    Article  CAS  PubMed  Google Scholar 

  48. Carra S, Rusmini P, Crippa V, Giorgetti E, Boncoraglio A, Cristofani R, Naujock M, Meister M et al (2013) Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders. Philos Trans Royal Soc B: Biol Sci 368(1617):20110409

    Article  Google Scholar 

  49. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92(3):351–366

    Article  CAS  PubMed  Google Scholar 

  50. Andley UP, Song Z, Wawrousek EF, Bassnett S (1998) The molecular chaperone αA-crystallin enhances lens epithelial cell growth and resistance to UVA stress. J Biol Chem 273(47):31252–31261

    Article  CAS  PubMed  Google Scholar 

  51. Mogk A, Deuerling E, Vorderwülbecke S, Vierling E, Bukau B (2003) Small heat shock proteins, ClpB and the DnaK system form a functional triade in reversing protein aggregation. Mol Microbiol 50(2):585–595

    Article  CAS  PubMed  Google Scholar 

  52. Lee S, Sowa ME, Watanabe YH, Sigler PB, Chiu W, Yoshida M, Tsai FTF (2003) The structure of ClpB: a molecular chaperone that rescues proteins from an aggregated state. Cell 115(2):229–240

    Article  CAS  PubMed  Google Scholar 

  53. Capo-Chichi JM, Boissel S, Brustein E, Pickles S, Fallet-Bianco C, Nassif C, Patry L, Dobrzeniecka S et al (2015) Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria. J Med Genet 52(5):303–311

    Article  CAS  PubMed  Google Scholar 

  54. Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94(1):73–82

    Article  CAS  PubMed  Google Scholar 

  55. Langklotz S, Baumann U, Narberhaus F (2012) Structure and function of the bacterial AAA protease FtsH. Biochimica Et Biophysica Acta (BBA)-Molecular. Cell Res 1823(1):40–48

    CAS  Google Scholar 

  56. Kaimal JM, Kandasamy G, Gasser F, Andréasson C (2017) Coordinated Hsp110 and Hsp104 activities power protein disaggregation in Saccharomyces cerevisiae. Mol Cell Biol 37(11):e00027–e00017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. DeSantis ME, Sweeny EA, Snead D, Leung EH, Go MS, Gupta K, Wendler P, Shorter J (2014) Conserved distal loop residues in the Hsp104 and ClpB middle domain contact nucleotide-binding domain 2 and enable Hsp70-dependent protein disaggregation. J Biol Chem 289(2):848–867

    Article  CAS  PubMed  Google Scholar 

  58. Lee J, Sung N, Yeo L, Chang C, Lee S, Tsai FTF (2017) Structural determinants for protein unfolding and translocation by the Hsp104 protein disaggregase. Biosci Rep 37(6):1–16

  59. Sosnick TR, Mayne L, Hiller R, Englander SW (1994) The barriers in protein folding. Nat Struct Biol 1(3):149–156

    Article  CAS  PubMed  Google Scholar 

  60. Uversky VN (2010) The mysterious unfoldome: structureless, underappreciated, yet vital part of any given proteome. J Biomed Biotechnol 2010: 568068:11–14

  61. Uversky VN (2010) Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D2 concept. Expert Rev Proteomics 7(4):543–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jahn TR, Radford SE (2005) The Yin and Yang of protein folding. FEBS J 272(23):5962–5970

    Article  CAS  PubMed  Google Scholar 

  63. Bartlett AI, Radford SE (2009) An expanding arsenal of experimental methods yields an explosion of insights into protein folding mechanisms. Nat Struct Mol Biol 16(6):582–588

    Article  CAS  PubMed  Google Scholar 

  64. Brockwell DJ, Radford SE (2007) Intermediates: ubiquitous species on folding energy landscapes? Curr Opin Struct Biol 17(1):30–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ellis RJ, Pinheiro TJT (2002) Danger—misfolding proteins. Nature 416(6880):483–484

    Article  CAS  PubMed  Google Scholar 

  66. Wetlaufer DB (1973) Nucleation, rapid folding, and globular intrachain regions in proteins. Proc Natl Acad Sci 70(3):697–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chaari A, Fahy C, Chevillot-Biraud A, Rholam M (2015) Insights into kinetics of agitation-induced aggregation of hen lysozyme under heat and acidic conditions from various spectroscopic methods. PLoS One 10(11):e0142095

    Article  PubMed  PubMed Central  Google Scholar 

  68. Muchowski PJ (2002) Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35(1):9–12

    Article  CAS  PubMed  Google Scholar 

  69. Arosio P, Knowles TPJ, Linse S (2015) On the lag phase in amyloid fibril formation. Phys Chem Chem Phys 17(12):7606–7618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zeineddine R, Yerbury JJ (2015) The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases. Front Physiol 6:277

    Article  PubMed  PubMed Central  Google Scholar 

  71. Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890

    Article  CAS  PubMed  Google Scholar 

  72. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319(5865):916–919

    Article  CAS  PubMed  Google Scholar 

  73. Mei J, Leung NLC, Kwok RTK, Lam JWY, Tang BZ (2015) Aggregation-induced emission: together we shine, united we soar! Chem Rev 115(21):11718–11940

    Article  CAS  PubMed  Google Scholar 

  74. Tutar Y, Özgür A, Tutar L, Tutar Y, Özgür A, Tutar L (2013) Role of protein aggregation in neurodegenerative diseases. Neurodegener Dis 55–76. https://doi.org/10.5772/54487

  75. Mymrikov EV, Seit-Nebi AS, Gusev NB (2011) Large potentials of small heat shock proteins. Physiol Rev 91(4):1123–1159

    Article  CAS  PubMed  Google Scholar 

  76. Sontag EM, Samant RS, Frydman J (2017) Mechanisms and functions of spatial protein quality control. Annu Rev Biochem 86:97–122

    Article  CAS  PubMed  Google Scholar 

  77. Weibezahn J, Schlieker C, Tessarz P, Mogk A, Bukau B (2005) Novel insights into the mechanism of chaperone-assisted protein disaggregation. Biol Chem 386(8):739–44

  78. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47(3):e147–e147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bercovich B, Stancovski I, Mayer A, Blumenfeld N, Laszlo A, Schwartz AL, Ciechanover A (1997) Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J Biol Chem 272(14):9002–9010

    Article  CAS  PubMed  Google Scholar 

  80. Carrion-Vazquez M, Li H, Lu H, Marszalek PE, Oberhauser AF, Fernandez JM (2003) The mechanical stability of ubiquitin is linkage dependent. Nat Struct Mol Biol 10(9):738–743

    Article  CAS  Google Scholar 

  81. Ciechanover A (2013) Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting. Bioorg Med Chem 21(12):3400–3410

    Article  CAS  PubMed  Google Scholar 

  82. Douglas PM, Summers DW, Cyr DM (2009) Molecular chaperones antagonize proteotoxicity by differentially modulating protein aggregation pathways. Prion 3(2):51–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ravikumar B, Sarkar S, Rubinsztein DC (2008) Clearance of mutant aggregate-prone proteins by autophagy. Autophagosome and Phagosome 445:195–211

  84. Kim HT, Goldberg AL (2017) The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin-independent proteolysis. J Biol Chem 292(23):9830–9839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kloetzel PM, Ossendorp F (2004) Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 16(1):76–81

    Article  CAS  PubMed  Google Scholar 

  86. Marino Gammazza A, Caruso Bavisotto C, Barone R, Macario ECD, Jl Macario A (2016) Alzheimer’s disease and molecular chaperones: current knowledge and the future of chaperonotherapy. Curr Pharm Des 22(26):4040–4049

    Article  PubMed  Google Scholar 

  87. Heck JW, Cheung SK, Hampton RY (2010) Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proc Natl Acad Sci 107(3):1106–1111

    Article  CAS  PubMed  Google Scholar 

  88. Kettern N, Dreiseidler M, Tawo R, Höhfeld J (2010) Chaperone-assisted degradation: multiple paths to destruction. Biol Chem 391(5):481–489

    Article  CAS  PubMed  Google Scholar 

  89. Gardner RG, Nelson ZW, Gottschling DE (2005) Degradation-mediated protein quality control in the nucleus. Cell 120(6):803–815

    Article  CAS  PubMed  Google Scholar 

  90. Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Höhfeld JR, Patterson C (2001) CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276(46):42938–42944

    Article  CAS  PubMed  Google Scholar 

  91. Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, Patterson C (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19(6):4535–4545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Höhfeld J, Patterson C (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3(1):93–96

    Article  CAS  PubMed  Google Scholar 

  93. Murata S, Minami Y, Minami M, Chiba T, Tanaka K (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2(12):1133–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Demand J, Alberti S, Patterson C, Höhfeld J (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11(20):1569–1577

    Article  CAS  PubMed  Google Scholar 

  95. Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. Sci World J 10:1543–1552

    Article  CAS  Google Scholar 

  96. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5(22):2592–2601

    Article  CAS  PubMed  Google Scholar 

  97. Takayama S, Bimston DN, Matsuzawa SI, Freeman BC, Aime-Sempe C, Xie Z, Morimoto RI, Reed JC (1997) BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J 16(16):4887–4896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Alberti S, Esser C, Höhfeld J (2003) BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress Chaperones 8(3):225–231

    Article  PubMed  PubMed Central  Google Scholar 

  99. Harding JJ, Beswick HT, Ajiboye R, Huby R, Blakytny R, Rixon KC (1989) Non-enzymic post-translational modification of proteins in aging. A review. Mech Ageing Dev 50(1):7–16

    Article  CAS  PubMed  Google Scholar 

  100. Wright HT (1991) Nonenzymatic deamidation of asparaginyl and glutaminyl residues in proteins. Crit Rev Biochem Mol Biol 26(1):1–52

    Article  CAS  PubMed  Google Scholar 

  101. Sun H, Gao J, Ferrington DA, Biesiada H, Williams TD, Squier TC (1999) Repair of oxidized calmodulin by methionine sulfoxide reductase restores ability to activate the plasma membrane Ca-ATPase. Biochemistry 38(1):105–112

    Article  CAS  PubMed  Google Scholar 

  102. Berlett BS, Levine RL, Stadtman ER (1996) Comparison of the effects of ozone on the modification of amino acid residues in glutamine synthetase and bovine serum albumin (∗). J Biol Chem 271(8):4177–4182

    Article  CAS  PubMed  Google Scholar 

  103. Duprat F, Guillemare E, Romey G, Fink M, Lesage F, Lazdunski M, Honore E (1995) Susceptibility of cloned K+ channels to reactive oxygen species. Proc Natl Acad Sci 92(25):11796–11800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yuh KC, Gafni A (1987) Reversal of age-related effects in rat muscle phosphoglycerate kinase. Proc Natl Acad Sci 84(21):7458–7462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Demchenko AP, Orlovska NN, Sukhomudrenko AG (1983) Age-dependent changes of protein structure: the properties of young and old rabbit aldolase are restored after reversible denaturation. Exp Gerontol 18(6):437–446

    Article  CAS  PubMed  Google Scholar 

  106. Stadtman ER (1992) Protein oxidation and aging. Science 257(5074):1220–1224

    Article  CAS  PubMed  Google Scholar 

  107. Monnier VM, Cerami A (1981) Nonenzymatic browning : possible process for aging of long-lived proteins. Science 211(4481):491–493

    Article  CAS  PubMed  Google Scholar 

  108. Conconi M, Szweda LI, Levine RL, Stadtman ER, Friguet B (1996) Age-related decline of rat liver multicatalytic proteinase activity and protection from oxidative inactivation by heat-shock protein 90. Arch Biochem Biophys 331(2):232–240

    Article  CAS  PubMed  Google Scholar 

  109. Heydari AR, Takahashi R, Gutsmann A, You S, Richardson A (1994) Hsp70 and aging. Experientia 50:1092–1098

    Article  CAS  PubMed  Google Scholar 

  110. Friguet B, Stadtman ER, Szweda LI (1994) Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal formation of cross-linked protein that inhibits the multicatalytic protease. J Biol Chem 269(34):21639–21643

    Article  CAS  PubMed  Google Scholar 

  111. Razzaque MS, Shimokawa I, Nazneen A, Higami Y, Taguchi T (1998) Age-related nephropathy in the Fischer 344 rat is associated with overexpression of collagens and collagen-binding heat shock protein 47. Cell Tissue Res 293:471–478

    Article  CAS  PubMed  Google Scholar 

  112. Rao DV, Watson K, Jones GL (1999) Age-related attenuation in the expression of the major heat shock proteins in human peripheral lymphocytes. Mech Ageing Dev 107(1):105–118

    Article  CAS  PubMed  Google Scholar 

  113. Nakanishi Y, Yasumoto K (1997) Induction after administering paraquat of heme oxygenase-1 and heat shock protein 70 in the liver of senescence-accelerated mice. Biosci Biotechnol Biochem 61(8):1302–1306

    Article  CAS  PubMed  Google Scholar 

  114. Niedzwiecki A, Kongpachith AM, Fleming JE (1991) Aging affects expression of 70-kDa heat shock proteins in Drosophila. J Biol Chem 266(14):9332–9338

    Article  CAS  PubMed  Google Scholar 

  115. Faassen AE, O'Leary JJ, Rodysill KJ, Bergh N, Hallgren HM (1989) Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors. Exp Cell Res 183(2):326–334

    Article  CAS  PubMed  Google Scholar 

  116. Fargnoli J, Kunisada T, Fornace AJ Jr, Schneider EL, Holbrook NJ (1990) Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci 87(2):846–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kregel KC, Moseley PL (1996) Differential effects of exercise and heat stress on liver HSP70 accumulation with aging. J Appl Physiol 80(2):547–551

    Article  CAS  PubMed  Google Scholar 

  118. Fleming JE, Walton JK, Dubitsky R, Bensch KG (1988) Aging results in an unusual expression of Drosophila heat shock proteins. Proc Natl Acad Sci 85(11):4099–4103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Locke M, Tanguay RM (1996) Diminished heat shock response in the aged myocardium. Cell Stress Chaperones 1(4):251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nitta Y, Abe K, Aoki M, Ohno I, Isoyama S (1994) Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Phys Heart Circ Phys 267(5):H1795–H1803

    CAS  Google Scholar 

  121. Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12(24):3788–3796

    Article  CAS  PubMed  Google Scholar 

  122. Cherian M, Abraham EC (1995) Decreased molecular chaperone property of α-crystallins due to posttranslational modifications. Biochem Biophys Res Commun 208(2):675–679

    Article  CAS  PubMed  Google Scholar 

  123. Davie CA (2008) A review of Parkinson's disease. Br Med Bull 86(1):109–127

    Article  CAS  PubMed  Google Scholar 

  124. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 26:1–58

    Article  Google Scholar 

  125. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501

    Article  CAS  PubMed  Google Scholar 

  126. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, Hyman BT (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of α-synuclein aggregation. J Neurochem 83(4):846–854

    Article  CAS  PubMed  Google Scholar 

  127. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 reduces α-synuclein aggregation and toxicity. J Biol Chem 279(24):25497–25502

    Article  CAS  PubMed  Google Scholar 

  128. Luk KC, Mills IP, Trojanowski JQ, Lee VMY (2008) Interactions between Hsp70 and the hydrophobic core of α-synuclein inhibit fibril assembly. Biochemistry 47(47):12614–12625

    Article  CAS  PubMed  Google Scholar 

  129. Hauser MA, Li YJ, Xu H, Noureddine MA, Shao YS, Gullans SR, Scherzer CR, Jensen RV et al (2005) Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol 62(6):917–921

    Article  PubMed  Google Scholar 

  130. Dedmon MM, Christodoulou J, Wilson MR, Dobson CM (2005) Heat shock protein 70 inhibits α-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 280(15):14733–14740

    Article  CAS  PubMed  Google Scholar 

  131. Huang C, Cheng H, Hao S, Zhou H, Zhang X, Gao J, Sun QH, Hu H et al (2006) Heat shock protein 70 inhibits α-synuclein fibril formation via interactions with diverse intermediates. J Mol Biol 364(3):323–336

    Article  CAS  PubMed  Google Scholar 

  132. Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8(11):1185–1186

    Article  CAS  PubMed  Google Scholar 

  133. Danzer KM, Ruf WP, Putcha P, Joyner D, Hashimoto T, Glabe C, Hyman BT, McLean PJ (2011) Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J 25(1):326–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhou Y, Gu G, Goodlett DR, Zhang T, Pan C, Montine TJ, Montine KS, Aebersold RH et al (2004) Analysis of α-synuclein-associated proteins by quantitative proteomics. J Biol Chem 279(37):39155–39164

    Article  CAS  PubMed  Google Scholar 

  135. Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2011) Molecular chaperones in Parkinson's disease–present and future. J Parkinsons Dis 1(4):299–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cascella R, Perni M, Chen SW, Fusco G, Cecchi C, Vendruscolo M, Chiti F, Dobson CM et al (2019) Probing the origin of the toxicity of oligomeric aggregates of α-synuclein with antibodies. ACS Chem Biol 14(6):1352–1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Falsone SF, Kungl AJ, Rek A, Cappai R, Zangger K (2009) The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein α-synuclein. J Biol Chem 284(45):31190–31199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Flower TR, Chesnokova LS, Froelich CA, Dixon C, Witt SN (2005) Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J Mol Biol 351(5):1081–1100

    Article  CAS  PubMed  Google Scholar 

  139. McLean PJ, Klucken J, Shin Y, Hyman BT (2004) Geldanamycin induces Hsp70 and prevents α-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321(3):665–669

    Article  CAS  PubMed  Google Scholar 

  140. Daturpalli S, Waudby CA, Meehan S, Jackson SE (2013) Hsp90 inhibits α-synuclein aggregation by interacting with soluble oligomers. J Mol Biol 425(22):4614–4628

    Article  CAS  PubMed  Google Scholar 

  141. Cristofani R, Crippa V, Vezzoli G, Rusmini P, Galbiati M, Cicardi ME, Meroni M, Ferrari V et al (2018) The small heat shock protein B8 (HSPB8) efficiently removes aggregating species of dipeptides produced in C9ORF72-related neurodegenerative diseases. Cell Stress Chaperones 23:1–12

    Article  CAS  PubMed  Google Scholar 

  142. Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet JC, Hyman BT, McLean PJ (2006) Small heat shock proteins protect against α-synuclein-induced toxicity and aggregation. Biochem Biophys Res Commun 351(3):631–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Rekas A, Adda CG, Aquilina JA, Barnham KJ, Sunde M, Galatis D, Williamson NA, Masters CL et al (2004) Interaction of the molecular chaperone αB-crystallin with α-synuclein: effects on amyloid fibril formation and chaperone activity. J Mol Biol 340(5):1167–1183

    Article  CAS  PubMed  Google Scholar 

  144. Cox D, Ecroyd H (2017) The small heat shock proteins αB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of α-synuclein. Cell Stress Chaperones 22:589–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14(4):248–264

    Article  CAS  PubMed  Google Scholar 

  146. Ince PG, Lowe J, Shaw PJ (1998) Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol 24(2):104–117

    Article  CAS  PubMed  Google Scholar 

  147. Kalmar B, Greensmith L (2017) Cellular chaperones as therapeutic targets in ALS to restore protein homeostasis and improve cellular function. Front Mol Neurosci 10:251

    Article  PubMed  PubMed Central  Google Scholar 

  148. Okado-Matsumoto A, Fridovich I (2002) Amyotrophic lateral sclerosis: a proposed mechanism. Proc Natl Acad Sci 99(13):9010–9014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shaw BF, Lelie HL, Durazo A, Nersissian AM, Xu G, Chan PK, Gralla EB, Tiwari A et al (2008) Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1. J Biol Chem 283(13):8340–8350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Liu J, Lillo C, Jonsson PA, Velde CV, Ward CM, Miller TM, Subramaniam JR, Rothstein JD et al (2004) Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43(1):5–17

    Article  CAS  PubMed  Google Scholar 

  151. James PA, Rankin J, Talbot K (2008) Asymmetrical late onset motor neuropathy associated with a novel mutation in the small heat shock protein HSPB1 (HSP27). J Neurol Neurosurg Psychiatry 79(4):461–463

    Article  CAS  PubMed  Google Scholar 

  152. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162(5):1066–1077

    Article  CAS  PubMed  Google Scholar 

  153. Patel YJK, Smith MDP, de Belleroche J, Latchman DS (2005) Hsp27 and Hsp70 administered in combination have a potent protective effect against FALS-associated SOD1-mutant-induced cell death in mammalian neuronal cells. Mol Brain Res 134(2):256–274

    Article  CAS  PubMed  Google Scholar 

  154. Geschwind MD (2015) Prion diseases. Continuum (Minneapolis, Minn.) 21(6 NEUROINFECTIOUS DISEASE):1612–38

  155. Prusiner SB (1998) Prions. Proc Natl Acad Sci 95(23):13363–13383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Krishnan J, Vannuvel K, Andries M, Waelkens E, Robberecht W, Van Den Bosch L (2008) Over-expression of Hsp27 does not influence disease in the mutant SOD1G93A mouse model of amyotrophic lateral sclerosis. J Neurochem 106(5):2170–2183

    Article  CAS  PubMed  Google Scholar 

  157. Liu J, Shinobu LA, Ward CM, Young D, Cleveland DW (2005) Elevation of the Hsp70 chaperone does not effect toxicity in mouse models of familial amyotrophic lateral sclerosis. J Neurochem 93(4):875–882

    Article  CAS  PubMed  Google Scholar 

  158. Novoselov SS, Mustill WJ, Gray AL, Dick JR, Kanuga N, Kalmar B, Greensmith L, Cheetham ME (2013) Molecular chaperone mediated late-stage neuroprotection in the SOD1G93A mouse model of amyotrophic lateral sclerosis. PLoS One 8(8):e73944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Takeuchi H, Kobayashi Y, Yoshihara T, Niwa JI, Doyu M, Ohtsuka K, Sobue G (2002) Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1. Brain Res 949(1-2):11–22

    Article  CAS  PubMed  Google Scholar 

  160. Shao J, Diamond MI (2007) Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet 16(R2):R115–R123

    Article  CAS  PubMed  Google Scholar 

  161. Zarouchlioti C, Parfitt DA, Li W, Gittings LM, Cheetham ME (2018) DNAJ Proteins in neurodegeneration: essential and protective factors. Philos Trans Royal Soc B: Biol Sci 373(1738):20160534

    Article  Google Scholar 

  162. Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19(2):148–154

    Article  CAS  PubMed  Google Scholar 

  163. Sharp P, Krishnan M, Pullar O, Navarrete R, Wells D, de Belleroche J (2006) Heat shock protein 27 rescues motor neurons following nerve injury and preserves muscle function. Exp Neurol 198(2):511–518

    Article  CAS  PubMed  Google Scholar 

  164. Blumen SC, Astord S, Robin V, Vignaud L, Toumi N, Cieslik A, Achiron A, Carasso RL et al (2012) A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Ann Neurol 71(4):509–519

    Article  CAS  PubMed  Google Scholar 

  165. Gess B, Auer-Grumbach M, Schirmacher A, Strom T, Zitzelsberger M, Rudnik-Schöneborn S, Röhr D, Halfter H et al (2014) HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. Neurology 83(19):1726–1732

    Article  CAS  PubMed  Google Scholar 

  166. Houlden H, Laura M, Wavrant-De Vrièze F, Blake J, Wood N, Reilly MM (2008) Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. Neurology 71(21):1660–1668

    Article  CAS  PubMed  Google Scholar 

  167. Ikeda Y, Abe A, Ishida C, Takahashi K, Hayasaka K, Yamada M (2009) A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation. J Neurol Sci 277(1-2):9–12

    Article  CAS  PubMed  Google Scholar 

  168. Rossor AM, Kalmar B, Greensmith L, Reilly MM (2012) The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry 83(1):6–14

    Article  PubMed  Google Scholar 

  169. Yerbury JJ, Gower D, Vanags L, Roberts K, Lee JA, Ecroyd H (2013) The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro. Cell Stress Chaperones 18:251–257

    Article  CAS  PubMed  Google Scholar 

  170. Irobi J, Impe KV, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, Vriendt ED et al (2004) Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 36(6):597–601

    Article  CAS  PubMed  Google Scholar 

  171. Eroglu B, Moskophidis D, Mivechi NF (2010) Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid β. Mol Cell Biol 30(19):4626–4643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Veereshwarayya V, Kumar P, Rosen KM, Mestril R, Querfurth HW (2006) Differential effects of mitochondrial heat shock protein 60 and related molecular chaperones to prevent intracellular β-amyloid-induced inhibition of complex IV and limit apoptosis. J Biol Chem 281(40):29468–29478

    Article  CAS  PubMed  Google Scholar 

  173. Shorter J (2008) Hsp104: a weapon to combat diverse neurodegenerative disorders. Neurosignals 16(1):63–74

    Article  CAS  PubMed  Google Scholar 

  174. Honjo K, Black SE, Verhoeff NPLG (2012) Alzheimer's disease, cerebrovascular disease, and the β-amyloid cascade. Can J Neurol Sci 39(6):712–728

    Article  PubMed  Google Scholar 

  175. Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF, Prado MAM (2017) The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front Neurosci 11:254

    Article  PubMed  PubMed Central  Google Scholar 

  176. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14(8):837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Rutledge BS, Choy WY, Duennwald ML (2022) Folding or holding?—Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease. J Biol Chem 298(5):1–13

  178. Perez N, Sugar J, Charya S, Johnson G, Merril C, Bierer L, Perl D, Haroutunian V et al (1991) Increased synthesis and accumulation of heat shock 70 proteins in Alzheimer's disease. Mol Brain Res 11(3-4):249–254

    Article  CAS  PubMed  Google Scholar 

  179. Wilhelmus MMM, Otte-Höller I, Wesseling P, De Waal RMW, Boelens WC, Verbeek MM (2006) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains. Neuropathol Appl Neurobiol 32(2):119–130

    Article  CAS  PubMed  Google Scholar 

  180. Evans CG, Wisén S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1–42) aggregation in vitro. J Biol Chem 281(44):33182–33191

    Article  CAS  PubMed  Google Scholar 

  181. Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S et al (2007) The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117(3):648–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Du H, Yan SS (2010) Mitochondrial permeability transition pore in Alzheimer's disease: cyclophilin D and amyloid beta. Biochimica et Biophysica Acta (BBA)-Mol Basis Dis 1802(1):198–204

    Article  CAS  Google Scholar 

  183. Auluck PK, Chan HYE, Trojanowski JQ, Lee VMY, Bonini NM (2002) Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556):865–868

    Article  CAS  PubMed  Google Scholar 

  184. Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8(6):933–941

    Article  CAS  PubMed  Google Scholar 

  185. Hamos JE, Oblas B, Pulaski-Salo D, Welch WJ, Bole DG, Drachman DA (1991) Expression of heat shock proteins in Alzheimer's disease. Neurology 41(3):345–345

    Article  CAS  PubMed  Google Scholar 

  186. Nemes Z, Devreese B, Steinert PM, Beeumen JV, Fésüs L (2004) Cross-linking of ubiquitin, HSP27, parkin and α-synuclein by γ-glutamyl-ε-lysine bonds in Alzheimer's neurofibrillary tangles. FASEB J 18(10):1135–1137

    Article  CAS  PubMed  Google Scholar 

  187. Emmanouilidou E, Stefanis L, Vekrellis K (2010) Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging 31(6):953–968

    Article  CAS  PubMed  Google Scholar 

  188. Riedel M, Goldbaum O, Schwarz L, Schmitt S, Richter-Landsberg C (2010) 17-AAG induces cytoplasmic α-synuclein aggregate clearance by induction of autophagy. PLoS One 5(1):e8753

    Article  PubMed  PubMed Central  Google Scholar 

  189. Putcha P, Danzer KM, Kranich LR, Scott A, Silinski M, Mabbett S, Hicks CD, Veal JM et al (2010) Brain-permeable small-molecule inhibitors of Hsp90 prevent α-synuclein oligomer formation and rescue α-synuclein-induced toxicity. J Pharmacol Exp Ther 332(3):849–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Casarejos MJ, Solano RM, Gomez A, Perucho J, De Yébenes JG, Mena MA (2011) The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells. Neurochem Int 58(4):512–520

    Article  CAS  PubMed  Google Scholar 

  191. Tradewell ML, Cooper LA, Minotti S, Durham HD (2011) Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: mechanistic relationship and differential sensitivity to intervention. Neurobiol Dis 42(3):265–275

    Article  CAS  PubMed  Google Scholar 

  192. Rusmini P, Simonini F, Crippa V, Bolzoni E, Onesto E, Cagnin M, Sau D, Ferri N et al (2011) 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. Neurobiol Dis 41(1):83–95

    Article  CAS  PubMed  Google Scholar 

  193. Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY, Beal MF (2006) Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis 2(5):246–254

    Article  Google Scholar 

  194. Gomes C, Escrevente C, Costa J (2010) Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett 475(3):145–149

    Article  CAS  PubMed  Google Scholar 

  195. Gifondorwa DJ, Robinson MB, Hayes CD, Taylor AR, Prevette DM, Oppenheim RW, Caress J, Milligan CE (2007) Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis. J Neurosci 27(48):13173–13180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hay DG, Sathasivam K, Tobaben S, Stahl B, Marber M, Mestril R, Mahal A, Smith DL 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(13):1389–1405

    Article  CAS  PubMed  Google Scholar 

  197. Herbst M, Wanker EE (2007) Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation. Neurodegener Dis 4(2-3):254–260

    Article  CAS  PubMed  Google Scholar 

  198. Tokui K, Adachi H, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J et al (2009) 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum Mol Genet 18(5):898–910

    Article  CAS  PubMed  Google Scholar 

  199. Katsuno M, Sang C, Adachi H, Minamiyama M, Waza M, Tanaka F, Doyu M, Sobue G (2005) Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci 102(46):16801–16806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E et al (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13(7):703–714

    Article  CAS  PubMed  Google Scholar 

  201. Paris D, Ganey NJ, Laporte V, Patel NS, Beaulieu-Abdelahad D, Bachmeier C, March A et al (2010) Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 7(1):1–15

    Article  Google Scholar 

  202. Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, de Yébenes JG et al (2010) Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis 39(3):423–438

    Article  PubMed  Google Scholar 

  203. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I et al (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci 95(11):6448–6453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Lesne SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH (2013) Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136(5):1383–1398

    Article  PubMed  PubMed Central  Google Scholar 

  205. Mandelkow EM, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2(7):a006247

    Article  PubMed  PubMed Central  Google Scholar 

  206. Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J et al (2007) Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci 104(22):9511–9516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70(1):503–533

    Article  CAS  PubMed  Google Scholar 

  208. Karagöz GE, Duarte AMS, Akoury E, Ippel H, Biernat J, Luengo TM, Radli M et al (2014) Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Cell 156(5):963–974

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This research work received funding from the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, through the project number ISP23-81.

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India

    Aditi Sharma, Om Prakash Shah & Lalit Sharma

  2. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 1444411, India

    Monica Gulati

  3. ARCCIM, Faculty of Health, University of Technology Sydney, Ultimo, NSW, 20227, Australia

    Monica Gulati

  4. Amity School of Pharmaceutical Sciences, Amity University, Mohali, Punjab, India, Amity University, Mohali, India

    Tapan Behl

  5. Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, 45142, Saudi Arabia

    Asaad Khalid & Syam Mohan

  6. Medicinal and Aromatic Plants Research Institute, National Center for Research, P.O. Box 2424, 11111, Khartoum, Sudan

    Asaad Khalid

  7. School of Health Sciences and Technology, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India

    Syam Mohan

  8. Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India

    Syam Mohan

  9. Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan, Saudi Arabia

    Asim Najmi & Khalid Zoghebi

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  1. Aditi Sharma
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Contributions

AS and TB: conceived the idea and wrote the first draft; OPS, LS, and MG: literature review and editing; AK and LS: figure work and revision; AN and KZ: editing; TB, SM, and AS: incorporating the changes in the initial draft, designing of the figures and proofread

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Correspondence to Tapan Behl or Syam Mohan.

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Highlights

• Neurodegenerative disorders result due to misfolded and aggregated proteins which accumulate and lead to neuronal dysfunction and ultimately neuronal death.

• By avoiding misfolding, aiding in protein folding, and enabling protein breakdown, molecular chaperones serve critical roles in preserving protein homeostasis.

• Molecular chaperones have also been linked to the pathophysiology of several neurological disorders including Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease.

• Molecular chaperones have become potential therapy targets concerning with the prevention and therapeutic approach for neuronal disorders.

• Effective therapies will likely involve modulating multiple components of the protein and it serves as the initial defense against misfolded proteins and an exciting prospect for therapeutic intervention.

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Sharma, A., Shah, O.P., Sharma, L. et al. Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03846-2

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