Small Heat Shock Proteins and Human Neurodegenerative Diseases

Abstract

The review discusses the role of small heat shock proteins (sHsps) in human neurodegenerative disorders, such as Charcot-Marie-Tooth disease (CMT), Parkinson’s and Alzheimer’s diseases, and different forms of tauopathies. The effects of CMT-associated mutations in two small heat shock proteins (HspB1 and HspB8) on the protein stability, oligomeric structure, and chaperone-like activity are described. Mutations in HspB1 shift the equilibrium between different protein oligomeric forms, leading to the alterations in its chaperone-like activity and interaction with protein partners, which can induce damage of the cytoskeleton and neuronal death. Mutations in HspB8 affect its interaction with the adapter protein Bag3, as well as the process of autophagy, also resulting in neuronal death. The impact of sHsps on different forms of amyloidosis is discussed. Experimental studies have shown that sHsps interact with monomers or small oligomers of amyloidogenic proteins, stabilize their structure, prevent their aggregation, and/or promote their specific proteolytic degradation. This effect might be due to the interaction between the β-strands of sHsps and β-strands of target proteins, which prevents aggregation of the latter. In cooperation with the other heat shock proteins, sHsps can promote disassembly of oligomers formed by amyloidogenic proteins. Despite significant achievements, further investigations are required for understanding the role of sHsps in protection against various neurodegenerative diseases.

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Abbreviations

ACD:

α-crystallin domain

CMT:

Charcot-Marie-Tooth disease

CTD:

C-terminal domain

NTD:

N-terminal domain

(s)Hsp:

(small) heat shock proteins

References

  1. 1.

    Vos, M. J., Hageman, J., Carra, S., and Kampinga, H. H. (2008) Structural and functional diversities between members of the human HSPB, HSPH, HSPA, and DNAJ chaperone families, Biochemistry, 47, 7001–7011; doi: https://doi.org/10.1021/bi800639z.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Vilasi, S., Bulone, D., Caruso Bavisotto, C., Campanella, C., Marino Gammazza, A., San Biagio, P. L., Cappello, F., Conway de Macario, E., and Macario, A. J. L. (2017) Chaperonin of group I: oligomeric spectrum and biochemical and biological implications, Front. Mol. Biosci., 4, 99; doi: https://doi.org/10.3389/fmolb.2017.00099.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  3. 3.

    Fontaine, J. M., Rest, J. S., Welsh, M. J., and Benndorf, R. (2003) The sperm outer dense fiber protein is the 10th member of the superfamily of mammalian small stress proteins, Cell Stress Chaperones, 8, 62–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Kappe, G., Franck, E., Verschuure, P., Boelens, W. C., Leunissen, J. A., and de Jong, W. W. (2003) The human genome encodes 10 alpha-crystallin-related small heat shock proteins: HspB1–10, Cell Stress Chaperones, 8, 53–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Mymrikov, E. V., Seit-Nebi, A. S., and Gusev, N. B. (2011) Large potentials of small heat shock proteins, Physiol. Rev., 91, 1123–1159; doi: 91/4/1123.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Bakthisaran, R., Tangirala, R., and Rao, C. M. (2015) Small heat shock proteins: role in cellular functions and pathology, Biochim. Biophys. Acta, 1854, 291–319; doi: https://doi.org/10.1016/j.bbapap.2014.12.019.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Bagneris, C., Bateman, O. A., Naylor, C. E., Cronin, N., Boelens, W. C., Keep, N. H., and Slingsby, C. (2009) Crystal structures of alpha-crystallin domain dimers of alphaB-crystallin and Hsp20, J. Mol. Biol., 392, 1242–1252; doi: S0022-2836(09)00936-X.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Baranova, E. V., Weeks, S. D., Beelen, S., Bukach, O. V., Gusev, N. B., and Strelkov, S. V. (2011) Three-dimensional structure of alpha-crystallin domain dimers of human small heat shock proteins HSPB1 and HSPB6, J. Mol. Biol., 411, 110–122; doi: S0022-2836(11)00574-2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Mymrikov, E. V., Seit-Nebi, A. S., and Gusev, N. B. (2012) Heterooligomeric complexes of human small heat shock proteins, Cell Stress Chaperones, 17, 157–169; doi: https://doi.org/10.1007/s12192-011-0296-0.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Delbecq, S. P., Rosenbaum, J. C., and Klevit, R. E. (2015) A mechanism of subunit recruitment in human small heat shock protein oligomers, Biochemistry, 54, 4276–4284; doi: https://doi.org/10.1021/acs.biochem.5b00490.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Heirbaut, M., Lermyte, F., Martin, E. M., Beelen, S., Sobott, F., Strelkov, S. V., and Weeks, S. D. (2017) Specific sequences in the N-terminal domain of human small heat-shock protein HSPB6 dictate preferential hetero-oligomerization with the orthologue HSPB1, J. Biol. Chem., 292, 9944–9957; doi: https://doi.org/10.1074/jbc.M116.773515.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Carver, J. A., Ecroyd, H., Truscott, R. J. W., Thorn, D. C., and Holt, C. (2018) Proteostasis and the regulation of intra- and extracellular protein aggregation by ATP-independent molecular chaperones: lens alpha-crystallins and milk caseins, Acc. Chem. Res., 51, 745–752; doi: https://doi.org/10.1021/acs.accounts.7b00250.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Garvey, M., Ecroyd, H., Ray, N. J., Gerrard, J. A., and Carver, J. A. (2017) Functional amyloid protection in the eye lens: retention of alpha-crystallin molecular chaperone activity after modification into amyloid fibrils, Biomolecules, 7, E67; doi: https://doi.org/10.3390/biom7030067.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Tanaka, N., Tanaka, R., Tokuhara, M., Kunugi, S., Lee, Y. F., and Hamada, D. (2008) Amyloid fibril formation and chaperone-like activity of peptides from alphaA-crystallin, Biochemistry, 47, 2961–2967; doi: https://doi.org/10.1021/bi701823g.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Delbecq, S. P., Jehle, S., and Klevit, R. (2012) Binding determinants of the small heat shock protein, alphaB-crystallin: recognition of the ‘IxI’ motif, EMBO J., 31, 4587–4594; doi: emboj2012318.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Hochberg, G. K., and Benesch, J. L. (2014) Dynamical structure of alphaB-crystallin, Prog. Biophys. Mol. Biol., 115, 11–20; doi: https://doi.org/10.1016/j.pbiomolbio.2014.03.003.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Jovcevski, B., Kelly, M. A., Rote, A. P., Berg, T., Gastall, H. Y., Benesch, J. L., Aquilina, J. A., and Ecroyd, H. (2015) Phosphomimics destabilize Hsp27 oligomeric assemblies and enhance chaperone activity, Chem. Biol., 22, 186–195; doi: https://doi.org/10.1016/j.chembiol.2015.01.001.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Muranova, L. K., Weeks, S. D., Strelkov, S. V., and Gusev, N. B. (2015) Characterization of mutants of human small heat shock protein HspB1 carrying replacements in the N-terminal domain and associated with hereditary motor neuron diseases, PLoS One, 10, e0126248; doi: https://doi.org/10.1371/journal.pone.0126248.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Sluchanko, N. N., Beelen, S., Kulikova, A. A., Weeks, S. D., Antson, A. A., Gusev, N. B., and Strelkov, S. V. (2017) Structural basis for the interaction of a human small heat shock protein with the 14-3-3 universal signaling regulator, Structure, 25, 305–316; doi: https://doi.org/10.1016/j.str.2016.12.005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Zwirowski, S., Klosowska, A., Obuchowski, I., Nillegoda, N. B., Pirog, A., Zietkiewicz, S., Bukau, B., Mogk, A., and Liberek, K. (2017) Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding, EMBO J., 36, 783–796; doi: https://doi.org/10.15252/embj.201593378.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Ahner, A., Gong, X., Schmidt, B. Z., Peters, K. W., Rabeh, W. M., Thibodeau, P. H., Lukacs, G. L., and Frizzell, R. A. (2013) Small heat shock proteins target mutant cystic fibrosis transmembrane conductance regulator for degradation via a small ubiquitin-like modifier-dependent pathway, Mol. Biol. Cell, 24, 74–84; doi: https://doi.org/10.1091/mbc.E12-09-0678.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Rusmini, P., Cristofani, R., Galbiati, M., Cicardi, M. E., Meroni, M., Ferrari, V., Vezzoli, G., Tedesco, B., Messi, E., Piccolella, M., Carra, S., Crippa, V., and Poletti, A. (2017) The role of the heat shock protein B8 (HSPB8) in motoneuron diseases, Front. Mol. Neurosci., 10, 176; doi: https://doi.org/10.3389/fnmol.2017.00176.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Carra, S., Crippa, V., Rusmini, P., Boncoraglio, A., Minoia, M., Giorgetti, E., Kampinga, H. H., and Poletti, A. (2012) Alteration of protein folding and degradation in motor neuron diseases: implications and protective functions of small heat shock proteins, Prog. Neurobiol., 97, 83–100; doi: S0301-0082(11)00176-6.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Torrente, M. P., and Shorter, J. (2013) The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins, Prion, 7, 457–463.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Weis, J., Claeys, K. G., Roos, A., Azzedine, H., Katona, I., Schroder, J. M., and Senderek, J. (2017) Towards a functional pathology of hereditary neuropathies, Acta Neuropathol., 133, 493–515; doi: https://doi.org/10.1007/s00401-016-1645-y.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Saporta, A. S., Sottile, S. L., Miller, L. J., Feely, S. M., Siskind, C. E., and Shy, M. E. (2011) Charcot-Marie-Tooth disease subtypes and genetic testing strategies, Ann. Neurol., 69, 22–33; doi: https://doi.org/10.1002/ana.22166.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Yoshimura, A., Yuan, J. H., Hashiguchi, A., Ando, M., Higuchi, Y., Nakamura, T., Okamoto, Y., Nakagawa, M., and Takashima, H. (2018) Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan, J. Neurol. Neurosurg. Psychiatry, 90, 195–202; doi: https://doi.org/10.1136/jnnp-2018-318839.

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Echaniz-Laguna, A., Geuens, T., Petiot, P., Pereon, Y., Adriaenssens, E., Haidar, M., Capponi, S., Maisonobe, T., Fournier, E., Dubourg, O., Degos, B., Salachas, F., Lenglet, T., Eymard, B., Delmont, E., Pouget, J., Juntas Morales, R., Goizet, C., Latour, P., Timmerman, V., and Stojkovic, T. (2017) Axonal neuropathies due to mutations in small heat shock proteins: clinical, genetic, and functional insights into novel mutations, Hum. Mutat., 38, 556–568; doi: https://doi.org/10.1002/humu.23189.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Adriaenssens, E., Geuens, T., Baets, J., Echaniz-Laguna, A., and Timmerman, V. (2017) Novel insights in the disease biology of mutant small heat shock proteins in neuromuscular diseases, Brain, 140, 2541–2549; doi: https://doi.org/10.1093/brain/awx187.

    PubMed  Article  Google Scholar 

  30. 30.

    Jovcevski, B., Kelly, M. A., Aquilina, J. A., Benesch, J. L. P., and Ecroyd, H. (2017) Evaluating the effect of phosphorylation on the structure and dynamics of Hsp27 dimers by means of ion mobility mass spectrometry, Anal. Chem., 89, 13275–13282; doi: https://doi.org/10.1021/acs.analchem.7b03328.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Clark, A. R., Lubsen, N. H., and Slingsby, C. (2012) sHSP in the eye lens: crystallin mutations, cataract and proteostasis, Int. J. Biochem. Cell Biol., 44, 1687–1697; doi: https://doi.org/10.1016/j.biocel.2012.02.015.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Nefedova, V. V., Sudnitsyna, M. V., Strelkov, S. V., and Gusev, N. B. (2013) Structure and properties of G84R and L99M mutants of human small heat shock protein HspB1 correlating with motor neuropathy, Arch. Biochem. Biophys., 538, 16–24; doi: https://doi.org/10.1016/j.abb.2013.07.028.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Nefedova, V. V., Datskevich, P. N., Sudnitsyna, M. V., Strelkov, S. V., and Gusev, N. B. (2013) Physico-chemical properties of R140G and K141Q mutants of human small heat shock protein HspB1 associated with hereditary peripheral neuropathies, Biochimie, 95, 1582–1592; doi: https://doi.org/10.1016/j.biochi.2013.04.014.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Weeks, S. D., Muranova, L. K., Heirbaut, M., Beelen, S., Strelkov, S. V., and Gusev, N. B. (2018) Characterization of human small heat shock protein HSPB1 alpha-crystallin domain localized mutants associated with hereditary motor neuron diseases, Sci. Rep., 8, 688; doi: https://doi.org/10.1038/s41598-017-18874-x.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Chalova, A. S., Sudnitsyna, M. V., Strelkov, S. V., and Gusev, N. B. (2014) Characterization of human small heat shock protein HspB1 that carries C-terminal domain mutations associated with hereditary motor neuron diseases, Biochim. Biophys. Acta, 1844, 2116–2126; doi: https://doi.org/10.1016/j.bbapap.2014.09.005.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Carver, J. A., Grosas, A. B., Ecroyd, H., and Quinlan, R. A. (2017) The functional roles of the unstructured N- and C-terminal regions in alphaB-crystallin and other mammalian small heat-shock proteins, Cell Stress Chaperones, 22, 627–638; doi: https://doi.org/10.1007/s12192-017-0789-6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Dahiya, V., and Buchner, J. (2019) Functional principles and regulation of molecular chaperones, Adv. Protein. Chem. Struct. Biol., 114, 1–60; doi: https://doi.org/10.1016/bs.apcsb.2018.10.001.

    PubMed  Article  Google Scholar 

  38. 38.

    Bucci, C., Bakke, O., and Progida, C. (2012) Charcot-Marie-Tooth disease and intracellular traffic, Prog. Neurobiol., 99, 191–225; doi: https://doi.org/10.1016/j.pneurobio.2012.03.003.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Pareyson, D., Saveri, P., Sagnelli, A., and Piscosquito, G. (2015) Mitochondrial dynamics and inherited peripheral nerve diseases, Neurosci. Lett., 596, 66–77; doi: https://doi.org/10.1016/j.neulet.2015.04.001.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Almeida-Souza, L., Asselbergh, B., d’Ydewalle, C., Moonens, K., Goethals, S., de Winter, V., Azmi, A., Irobi, J., Timmermans, J. P., Gevaert, K., Remaut, H., Van Den Bosch, L., Timmerman, V., and Janssens, S. (2011) Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy, J. Neurosci., 31, 15320–15328; doi: 31/43/15320.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    d’Ydewalle, C., Krishnan, J., Chiheb, D. M., Van Damme, P., Irobi, J., Kozikowski, A. P., Vanden Berghe, P., Timmerman, V., Robberecht, W., and Van Den Bosch, L. (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease, Nat. Med., 17, 968–974; doi: https://doi.org/10.1038/nm.2396.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Benedetti, S., Previtali, S. C., Coviello, S., Scarlato, M., Cerri, F., Di Pierri, E., Piantoni, L., Spiga, I., Fazio, R., Riva, N., Natali Sora, M. G., Dacci, P., Malaguti, M. C., Munerati, E., Grimaldi, L. M., Marrosu, M. G., De Pellegrin, M., Ferrari, M., Comi, G., Quattrini, A., and Bolino, A. (2010) Analyzing histopathological features of rare Charcot-Marie-Tooth neuropathies to unravel their pathogenesis, Arch. Neurol., 67, 1498–1505; doi: https://doi.org/10.1001/archneurol.2010.303.

    PubMed  Article  Google Scholar 

  43. 43.

    Almeida-Souza, L., Timmerman, V., and Janssens, S. (2011) Microtubule dynamics in the peripheral nervous system: a matter of balance, Bioarchitecture, 1, 267–270; doi: https://doi.org/10.4161/bioa.1.6.19198.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Benoy, V., Vanden Berghe, P., Jarpe, M., Van Damme, P., Robberecht, W., and Van Den Bosch, L. (2017) Development of improved HDAC6 inhibitors as pharmacological therapy for axonal Charcot-Marie-Tooth disease, Neurotherapeutics, 14, 417–428; doi: https://doi.org/10.1007/s13311-016-0501-z.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Zhai, J., Lin, H., Julien, J. P., and Schlaepfer, W. W. (2007) Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1, Hum. Mol. Genet., 16, 3103–3116; doi: https://doi.org/10.1093/hmg/ddm272.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Ackerley, S., James, P. A., Kalli, A., French, S., Davies, K. E., and Talbot, K. (2006) A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes, Hum. Mol. Genet., 15, 347–354; doi: https://doi.org/10.1093/hmg/ddi452.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Holmgren, A., Bouhy, D., De Winter, V., Asselbergh, B., Timmermans, J. P., Irobi, J., and Timmerman, V. (2013) Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments, Acta Neuropathol., 126, 93–108; doi: https://doi.org/10.1007/s00401-013-1133-6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Srivastava, A. K., Renusch, S. R., Naiman, N. E., Gu, S., Sneh, A., Arnold, W. D., Sahenk, Z., and Kolb, S. J. (2012) Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice, Neurobiol. Dis., 47, 163–173; doi: S0969-9961(12)00124-6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Lee, J., Jung, S. C., Joo, J., Choi, Y. R., Moon, H. W., Kwak, G., Yeo, H. K., Lee, J. S., Ahn, H. J., Jung, N., Hwang, S., Rheey, J., Woo, S. Y., Kim, J. Y., Hong, Y. B., and Choi, B. O. (2015) Overexpression of mutant HSP27 causes axonal neuropathy in mice, J. Biomed. Sci., 22, 43; doi: https://doi.org/10.1186/s12929-015-0154-y.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Kim, M. V., Seit-Nebi, A. S., Marston, S. B., and Gusev, N. B. (2004) Some properties of human small heat shock protein Hsp22 (H11 or HspB8), Biochem. Biophys. Res. Commun., 315, 796–801; doi: https://doi.org/10.1016/j.bbrc.2004.01.130.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Chowdary, T. K., Raman, B., Ramakrishna, T., and Rao, C. M. (2004) Mammalian Hsp22 is a heat-inducible small heat-shock protein with chaperone-like activity, Biochem. J., 381, 379–387; doi: https://doi.org/10.1042/BJ20031958.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Kim, M. V., Kasakov, A. S., Seit-Nebi, A. S., Marston, S. B., and Gusev, N. B. (2006) Structure and properties of K141E mutant of small heat shock protein HSP22 (HspB8, H11) that is expressed in human neuromuscular disorders, Arch. Biochem. Biophys., 454, 32–41; doi: S0003-9861(06)00267-0.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Shemetov, A. A., and Gusev, N. B. (2011) Biochemical characterization of small heat shock protein HspB8 (Hsp22)-Bag3 interaction, Arch. Biochem. Biophys., 513, 1–9; doi: S0003-9861(11)00249-9.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Carra, S., Boncoraglio, A., Kanon, B., Brunsting, J. F., Minoia, M., Rana, A., Vos, M. J., Seidel, K., Sibon, O. C., and Kampinga, H. H. (2010) Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases, J. Biol. Chem., 285, 37811–37822; doi: https://doi.org/10.1074/jbc.M110.127498.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Haidar, M., Asselbergh, B., Adriaenssens, E., De Winter, V., Timmermans, J. P., Auer-Grumbach, M., Juneja, M., and Timmerman, V. (2019) Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies, Autophagy, 15, 1051–1068; doi: https://doi.org/10.1080/15548627.2019.1569930.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Sharma, S. K., and Priya, S. (2017) Expanding role of molecular chaperones in regulating alpha-synuclein mis-folding; implications in Parkinson’s disease, Cell. Mol. Life Sci., 74, 617–629; doi: https://doi.org/10.1007/s00018-016-2340-9.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Cox, D., Carver, J. A., and Ecroyd, H. (2014) Preventing alpha-synuclein aggregation: the role of the small heat-shock molecular chaperone proteins, Biochim. Biophys. Acta, 1842, 1830–1843; doi: https://doi.org/10.1016/j.bbadis.2014.06.024.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Leak, R. K. (2014) Heat shock proteins in neurodegenerative disorders and aging, J. Cell Commun. Signal., 8, 293–310; doi: https://doi.org/10.1007/s12079-014-0243-9.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Cox, D., Selig, E., Griffin, M. D., Carver, J. A., and Ecroyd, H. (2016) Small heat-shock proteins prevent alpha-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation, J. Biol. Chem., 291, 22618–22629; doi: https://doi.org/10.1074/jbc.M116.739250.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Cox, D., and Ecroyd, H. (2017) The small heat shock proteins alphaB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of alpha-synuclein, Cell Stress Chaperones, 22, 589–600; doi: https://doi.org/10.1007/s12192-017-0785-x.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Cox, D., Whiten, D. R., Brown, J. W. P., Horrocks, M. H., San Gil, R., Dobson, C. M., Klenerman, D., van Oijen, A. M., and Ecroyd, H. (2018) The small heat shock protein Hsp27 binds alpha-synuclein fibrils, preventing elongation and cytotoxicity, J. Biol. Chem., 293, 4486–4497; doi: https://doi.org/10.1074/jbc.M117.813865.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Mainz, A., Peschek, J., Stavropoulou, M., Back, K. C., Bardiaux, B., Asami, S., Prade, E., Peters, C., Weinkauf, S., Buchner, J., and Reif, B. (2015) The chaperone alphaB-crystallin uses different interfaces to capture an amorphous and an amyloid client, Nat. Struct. Mol. Biol., 22, 898–905; doi: https://doi.org/10.1038/nsmb.3108.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Alperstein, A. M., Ostrander, J. S., Zhang, T. O., and Zanni, M. T. (2019) Amyloid found in human cataracts with two-dimensional infrared spectroscopy, Proc. Natl. Acad. Sci. USA, 116, 6602–6607; doi: https://doi.org/10.1073/pnas.1821534116.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Lu, S. Z., Guo, Y. S., Liang, P. Z., Zhang, S. Z., Yin, S., Yin, Y. Q., Wang, X. M., Ding, F., Gu, X. S., and Zhou, J. W. (2019) Suppression of astrocytic autophagy by alphaB-crystallin contributes to alpha-synuclein inclusion formation, Transl. Neurodegener., 8, 3; doi: https://doi.org/10.1186/s40035-018-0143-7.

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Boros, S., Kamps, B., Wunderink, L., de Bruijn, W., de Jong, W. W., and Boelens, W. C. (2004) Transglutaminase catalyzes differential crosslinking of small heat shock proteins and amyloid-beta, FEBS Lett., 576, 57–62; doi: S0014579304010816.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Wilhelmus, M. M., Otte-Holler, I., Wesseling, P., de Waal, R. M., Boelens, W. C., and Verbeek, M. M. (2006) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer’s disease brains, Neuropathol. Appl. Neurobiol., 32, 119–130; doi: https://doi.org/10.1111/j.1365-2990.2006.00689.x.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Zerovnik, E. (2017) Co-chaperoning by amyloid-forming proteins: cystatins vs. crystallins, Eur. Biophys. J., 46, 789–793; doi: https://doi.org/10.1007/s00249-017-1214-x.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Nafar, F., Williams, J. B., and Mearow, K. M. (2016) Astrocytes release HspB1 in response to amyloid-beta exposure in vitro, J. Alzheimers Dis., 49, 251–263; doi: https://doi.org/10.3233/JAD-150317.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Wilhelmus, M. M., Boelens, W. C., Otte-Holler, I., Kamps, B., de Waal, R. M., and Verbeek, M. M. (2006) Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity, Brain Res., 1089, 67–78; doi: S0006-8993(06)00762-1.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Cameron, R. T., Quinn, S. D., Cairns, L. S., MacLeod, R., Samuel, I. D., Smith, B. O., Carlos Penedo, J., and Baillie, G. S. (2014) The phosphorylation of Hsp20 enhances its association with amyloid-beta to increase protection against neuronal cell death, Mol. Cell. Neurosci., 61, 46–55; doi: https://doi.org/10.1016/j.mcn.2014.05.002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Sotiropoulos, I., Galas, M. C., Silva, J. M., Skoulakis, E., Wegmann, S., Maina, M. B., Blum, D., Sayas, C. L., Mandelkow, E. M., Mandelkow, E., Spillantini, M. G., Sousa, N., Avila, J., Medina, M., Mudher, A., and Buee, L. (2017) Atypical, non-standard functions of the microtubule associated tau protein, Acta Neuropathol. Commun., 5, 91; doi: https://doi.org/10.1186/s40478-017-0489-6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Sierra-Fonseca, J. A., and Gosselink, K. L. (2018) Tauopathy and neurodegeneration: a role for stress, Neurobiol. Stress, 9, 105–112; doi: https://doi.org/10.1016/j.ynstr.2018.08.009.

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Zabik, N. L., Imhof, M. M., and Martic-Milne, S. (2017) Structural evaluations of tau protein conformation: methodologies and approaches, Biochem. Cell Biol., 95, 338–349; doi: https://doi.org/10.1139/bcb-2016-0227.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Shimura, H., Miura-Shimura, Y., and Kosik, K. S. (2004) Binding of tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival, J. Biol. Chem., 279, 17957–17962; doi: https://doi.org/10.1074/jbc.M400351200.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Kumar, P., Jha, N. K., Jha, S. K., Ramani, K., and Ambasta, R. K. (2015) Tau phosphorylation, molecular chaperones, and ubiquitin E3 ligase: clinical relevance in Alzheimer’s disease, J. Alzheimers Dis., 43, 341–361; doi: https://doi.org/10.3233/JAD-140933.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Abisambra, J. F., Blair, L. J., Hill, S. E., Jones, J. R., Kraft, C., Rogers, J., Koren, J., 3rd, Jinwal, U. K., Lawson, L., Johnson, A. G., Wilcock, D., O’Leary, J. C., Jansen-West, K., Muschol, M., Golde, T. E., Weeber, E. J., Banko, J., and Dickey, C. A. (2010) Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice, J. Neurosci., 30, 15374–15382; doi: https://doi.org/10.1523/JNEUROSCI.3155-10.2010.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Baughman, H. E. R., Clouser, A. F., Klevit, R. E., and Nath, A. (2018) HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation, J. Biol. Chem., 293, 2687–2700; doi: https://doi.org/10.1074/jbc.M117.803411.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Janowska, M. K., Baughman, H. E. R., Woods, C. N., and Klevit, R. E. (2019) Mechanisms of small heat shock proteins, Cold Spring Harb. Perspect. Biol., a034025; doi: https://doi.org/10.1101/cshperspect.a034025.

    PubMed  Article  Google Scholar 

  79. 79.

    Hashiguchi, M., Sobue, K., and Paudel, H. K. (2000) 14-3-3zeta is an effector of tau protein phosphorylation, J. Biol. Chem., 275, 25247–25254; doi: https://doi.org/10.1074/jbc.M003738200.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Sadik, G., Tanaka, T., Kato, K., Yamamori, H., Nessa, B. N., Morihara, T., and Takeda, M. (2009) Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation, J. Neurochem., 108, 33–43; doi: https://doi.org/10.1111/j.1471-4159.2008.05716.x.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Sluchanko, N. N., Seit-Nebi, A. S., and Gusev, N. B. (2009) Effect of phosphorylation on interaction of human tau protein with 14-3-3zeta, Biochem. Biophys. Res. Commun., 379, 990–994; doi: S0006-291X(09)00007-2.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Sluchanko, N. N., Seit-Nebi, A. S., and Gusev, N. B. (2009) Phosphorylation of more than one site is required for tight interaction of human tau protein with 14-3-3zeta, FEBS Lett., 583, 2739–2742; doi: S0014-5793(09)00593-6.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Sluchanko, N. N., and Gusev, N. B. (2011) Probable participation of 14-3-3 in tau protein oligomerization and aggregation, J. Alzheimers Dis., 27, 467–476; doi: https://doi.org/10.3233/JAD-2011-110692.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Sluchanko, N. N., Sudnitsyna, M. V., Chernik, I. S., Seit-Nebi, A. S., and Gusev, N. B. (2011) Phosphomimicking mutations of human 14-3-3zeta affect its interaction with tau protein and small heat shock protein HspB6, Arch. Biochem. Biophys., 506, 24–34; doi: S0003-9861(10)00463-7.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Wang, K., Zhang, J., Xu, Y., Ren, K., Xie, W. L., Yan, Y. E., Zhang, B. Y., Shi, Q., Liu, Y., and Dong, X. P. (2013) Abnormally upregulated alphaB-crystallin was highly coincidental with the astrogliosis in the brains of scrapie-infected hamsters and human patients with prion diseases, J. Mol. Neurosci., 51, 734–748; doi: https://doi.org/10.1007/s12031-013-0057-x.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Duennwald, M. L., Echeverria, A., and Shorter, J. (2012) Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans, PLoS Biol., 10, e1001346; doi: https://doi.org/10.1371/journal.pbio.1001346.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Rothbard, J. B., Rothbard, J. J., Soares, L., Fathman, C. G., and Steinman, L. (2018) Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine, Proc. Natl. Acad. Sci. USA, 115, 7081–7086; doi: https://doi.org/10.1073/pnas.1804599115.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Rothbard, J. B., Kurnellas, M. P., Ousman, S. S., Brownell, S., Rothbard, J. J., and Steinman, L. (2018) Small heat shock proteins, amyloid fibrils, and nicotine stimulate a common immune suppressive pathway with implications for future therapies, Cold Spring Harb. Perspect. Med., 9, a034223; doi: https://doi.org/10.1101/cshperspect.a034223.

    Article  Google Scholar 

  89. 89.

    Liu, Z., Wang, C., Li, Y., Zhao, C., Li, T., Li, D., Zhang, S., and Liu, C. (2018) Mechanistic insights into the switch of alphaB-crystallin chaperone activity and self-multimerization, J. Biol. Chem., 293, 14880–14890; doi: https://doi.org/10.1074/jbc.RA118.004034.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

All authors of this paper are alumni of the Department of Biochemistry, School of Biology, Moscow State University. Our investigation would have been impossible if not based on the knowledge and skills obtained in the course of our study at our department, on traditions laid by the founder of our department Academician Sergei E. Severin. In the year of the 80th anniversary of the Department of Biochemistry, we would like to wish our department great achievements and to voice the hope that in the future, despite all difficulties, the Department of Biochemistry will be able to educate interested and skillful biochemists.

Funding

This study was supported by the Russian Foundation for Basic Research (project 19-04-00038).

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Correspondence to N. B. Gusev.

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The authors declare no conflict of interest in financial or any other area.

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This article does not contain studies with human participants or animals performed by any of the authors.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 11, pp. 1564–1577.

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Muranova, L.K., Ryzhavskaya, A.S., Sudnitsyna, M.V. et al. Small Heat Shock Proteins and Human Neurodegenerative Diseases. Biochemistry Moscow 84, 1256–1267 (2019). https://doi.org/10.1134/S000629791911004X

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Keywords

  • small heat shock proteins
  • chaperone-like activity
  • amorphous aggregation
  • β-amyloids
  • posttranslational modifications
  • neurodegenerative diseases