Heat Shock Protein70 in Neurological Disease

  • Pinar Ortan
  • Ozden Yildirim Akan
  • Ferda Hosgorler
Part of the Heat Shock Proteins book series (HESP, volume 14)


The HSP70 is a chaperon protein that is expressed during stress conditions that participates in many biological processes, including protein trafficking, nascent polypeptide folding and the refolding of the wrong proteins and cleaning of the misfolded ones. The expression is increased during various pathological conditions such as cerebral ischemia, neurodegenerative diseases, epilepsy, and trauma. They are found in both intracellular and extracellular compartments. HSP70 exhibits different functions in accordance with its location. Intracellular HSP70 exerts cytoprotective functions as a chaperone protein, whereas extracellular HSP70 exerts immunomodulatory functions that trigger immunological responses. They play an auxiliary role in antigen presentation in the appearance of immunological response in multiple sclerosis. Epilepsy is thought to have emerged as a stressor. HSP overexpression is proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. In this chapter, we wanted to summarize the recent studies on the role of HSP70 in neurological disorders.


Alzheimer disease Heat shock protein 70 Hsp70 Neurological disorders Neuroprotection 


Amiloid beta


Amyotrophic Lateral Sclerosis


Creutzfeldt-Jakob disease




Experimental allegic encephalomyelitis


Fatal familial insomnia


Gerstmann-Sträussler-Scheinker syndrome


Huntington disease


Heat shock protein


Leucine-rich repeat kinase-2


Myasthenia gravis


Multiple sclerosis


Mesial temporal sclerosis


Parkinson’s disease


PTEN-induced putative kinase 1




Cellular prion associated proteins


Disease associated prion proteins




Tar DNA binding protein 43


Ubiquitin-proteasome system


Variant Creutzfeldt-Jakob disease



We would like to thank the editorial staff for the opportunity of being able to be among the authors of the book.


  1. Ahmad, A. (2010). DnaK/DnaJ/GrpE of HSP70 system have differing effects on alpha-synuclein fibrillation involved in Parkinson’s disease. International Journal of Biological Macromolecules, 46(2), 275–279.CrossRefPubMedGoogle Scholar
  2. Ammon-Treiber, S., Grecksch, G., Angelidis, C., et al. (2007). Pentylenetetrazol kindling in mice overexpressing heat shock protein 70. Naunyn-Schmiedeberg’s Arch Pharmacol, 375, 115–112.CrossRefGoogle Scholar
  3. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., et al. (2002). Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science, 295(5556), 865–868.CrossRefPubMedGoogle Scholar
  4. Bersuker, K., Hipp, M. S., Calamini, B., et al. (2013). Heat shock response activation exacerbates inclusion body formation in a cellular model of Huntington disease. The Journal of Biological Chemistry, 288, 23633–23638.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boiocchi, C., Monti, M. C., Osera, C., et al. (2016). Heat shock protein 70-hom gene polymorphism and protein expression in multiple sclerosis. Journal of Neuroimmunology, 298, 189–193.CrossRefPubMedGoogle Scholar
  6. Budka, H. (2003). Neuropathology of prion diseases. British Medical Bulletin, 66, 121–130.CrossRefPubMedGoogle Scholar
  7. Cassu, D., Masala, S., Frau, J., et al. (2013). Anti Mycobacterium avium subsp. Paratuberculosis heat shock protein 70 antibodies in sera of Sardinian patients with multiple sclerosis. Journal of the Neurological Sciences, 355(1–2), 131–133.CrossRefGoogle Scholar
  8. Chen, S., & Brown, I. R. (2007). Neuronal expression of constitutive heat shock proteins: Implications for neurodegenerative diseases. Cell Stress & Chaperones, 12(1), 51–58.CrossRefGoogle Scholar
  9. Chiba, S., Yokota, S., Yonekura, K., et al. (2006). Autoantibodies against HSP70 family proteins were detected in the cerebrospinal fluid from patients with multiple sclerosis. Journal of the Neurological Sciences, 241(1–2), 39–43.CrossRefPubMedGoogle Scholar
  10. Ciechanover, A., & Kwon, Y. T. (2015). Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies. Experimental & Molecular Medicine, 47, 147.CrossRefGoogle Scholar
  11. Coban, P., Çe, P., Erkizan, O., & Gedizlioglu, M. (2011). Heat shock protein 27 in migraine patients. Journal of Neurological Sciences [Turkish], 28(1), 28–34.Google Scholar
  12. Davies, S. W., Turmaine, M., Cozens, B. A., et al. (1997). Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell, 90(3), 537–548.CrossRefPubMedGoogle Scholar
  13. Davies, S. W., Beardsall, K., Turmaine, M., et al. (1998). Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? Lancet, 351, 131.CrossRefPubMedGoogle Scholar
  14. Desler, C., Lillenes, M. S., Tønjum, T., et al. (2017). The role of mitochondrial dysfunction in the progression of Alzheimer’s disease. Current Medicinal Chemistry. [Epub ahead of print].
  15. Diedrich, J. F., Carp, R. I., & Haase, A. T. (1993). Increased expression of heat shock protein, transferrin, and beta 2-microglobulin in astrocytes during scrapie. Microbial Pathogenesis, 15, 1–6.CrossRefPubMedGoogle Scholar
  16. Fiszer, U., Fredrikson, S., & Członkowska, A. (1996). Humoral response to HSP 65 and HSP 70 in cerebrospinal fluid in Parkinson’s disease. Journal of the Neurological Sciences, 139(1), 66–70.CrossRefPubMedGoogle Scholar
  17. Gómez-Chocoa, M., Doucerain, C., Urra, X., et al. (2014). Presence of heat shock protein 70 in secondary lymphoid tissue correlates with stroke prognosis. Journal of Neuroimmunology, 270(1–2), 67–74.CrossRefGoogle Scholar
  18. Halliday, G. M., Holton, J. L., Revesz, T., et al. (2011). Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathologica, 122, 187–204.CrossRefPubMedGoogle Scholar
  19. Helgeland, G., Petzold, A., Hoff, J. M., et al. (2010). Anti-heat shock protein 70 antibody levels are increased in myasthenia gravis and Guillain-Barré syndrome. Journal of Neuroimmunology, 225(1–2), 180–183.CrossRefPubMedGoogle Scholar
  20. Hernández-Pedro, N. Y., Espinosa-Ramirez, G., de la Cruz, V. P., et al. (2013). Initial immunopathogenesis of multiple sclerosis: Innate immune response. Clinical and Developmental Immunology. Article ID 413465, 15 pages.Google Scholar
  21. Ho, A. K., & Hocaoglu, M. B. (2011). Impact of Huntington’s across the entire disease spectrum: The phases and stages of disease from the patient perspective. Clinical Genetics, 80(3), 235–239.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ho, S. L., Poon, C. Y., Lin, C., et al. (2015). Inhibition of β-amyloid aggregation By albiflorin, aloeemodin and neohesperidin and their neuroprotective effect on primary hippocampal cells against β-amyloid induced toxicity. Current Alzheimer Research, 12(5), 424–433.CrossRefPubMedGoogle Scholar
  23. Huang, C., Cheng, H., Hao, S., et al. (2006). Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverseintermediates. Journal of Molecular Biology, 364(3), 323–336.CrossRefPubMedGoogle Scholar
  24. Hung, S. Y., & Fu, W. M. (2017). Drug candidates in clinical trials for Alzheimer’s disease. Biomedical Science, 24(1), 47.CrossRefGoogle Scholar
  25. Huntington, G. (1872). Med Surg Report 26, 320.Google Scholar
  26. Jones, G., Song, Y., Chung, S., et al. (2004). Propagation of Saccharomyces cerevisiae [PSI+] prion is impaired by factors that regulate HSP70 substrate binding. Molecular and Cellular Biology, 24(9), 3928–3937.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kacimi, R., & Yenari, M. A. (2015). Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells. Glia, 63(7), 1200–1212.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kalmar, B., & Greensmith, L. (2017). Cellular chaperones as therapeutic targets in ALS to restore protein homeostasis and improve cellular function. Frontiers in Molecular Neuroscience, 10, 251. Scholar
  29. Kandratavicius, L., Hallak, J. E., Carlotti, C. G., et al. (2014). Hippocampal expression of heat shock proteins in mesial temporal lobe epilepsy with psychiatric comorbidities and their relation to seizure outcome. Epilepsia, 55, 1834–1843.CrossRefPubMedGoogle Scholar
  30. Kazemi-Esfarjani, P., & Benzer, S. (2002). Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1. Human Molecular Genetics, 11(21), 2657–2672.CrossRefPubMedGoogle Scholar
  31. Kenward, N., Hope, J., Landon, M., et al. (1994). Expression of polyubiquitin and heat-shock protein 70 genes increases in the later stages of disease progression in scrapie-infected mouse brain. Journal of Neurochemistry, 62, 1870–1877.CrossRefPubMedGoogle Scholar
  32. Kim, J. Y., Kim, N., Zheng, Z., et al. (2016). 70kDa heat shock protein downregulates dynamin in experimental stroke: A new therapeutic target? Stroke, 47(8), 2003–2011.CrossRefGoogle Scholar
  33. King, C. Y., Tittmann, P., Gross, H., et al. (1997). Prion-inducing domain 2-114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments. Proceedings of the National Academy of Sciences of the United States of America, 94(13), 6618–6622.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Klucken, J., Shin, Y., Masliah, E., et al. (2004). HSP70 reduces alpha-synuclein aggregation and toxicity. The Journal of Biological Chemistry, 279(24), 25497–25502.CrossRefPubMedGoogle Scholar
  35. Krüger, R., Kuhn, W., Müller, T., et al. (1998). Ala30Pro mutation in the gene encoding alpha synuclein in Parkinson’s disease. Nature Genetics, 18(2), 106–108.CrossRefPubMedGoogle Scholar
  36. Lu, R. C., Tan, M. S., Wang, H., et al. (2014). Heat shock protein 70 in Alzheimer’s disease. BioMed Research International, 2014, 435203. Scholar
  37. Lucchinetti, C., Brück, W., Parisi, J., et al. (2000). Heterogenity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Annals of Neurology, 47(6), 707–717.CrossRefPubMedGoogle Scholar
  38. Mansilla, M. J., Costa, C., Eixarch, H., et al. (2014). HSP70 regulates immune response in experimental autoimmune encephalomyelitis. PLoS One, 9(8). Scholar
  39. Monsellier, E., Redeker, V., Ruiz-Arlandis, G., et al. (2015). Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation. The Journal of Biological Chemistry, 290(5), 2560–2576.CrossRefPubMedGoogle Scholar
  40. Muchowski, P. J., & Wacker, J. L. (2005). Modulation of neurodegeneration by molecular chaperones. Nature Reviews. Neuroscience, 6(1), 11–22.CrossRefPubMedGoogle Scholar
  41. Munakata, S., Chen, M., Aosai, F., et al. (2008). The clinical significance of anti-heat shock cognate protein 71 antibody in myasthenia gravis. Journal of Clinical Neuroscience, 15(2), 158–165.CrossRefPubMedGoogle Scholar
  42. Namba, Y., Tomonaga, M., Ohtsuka, K., et al. (1991). HSP 70 is associated with abnormal cytoplasmic inclusions characteristic of neurodegenerative diseases. Nō to Shinkei, 43(1), 57–60.PubMedGoogle Scholar
  43. Patterson, K. R., Ward, S. M., Combs, B., et al. (2011). Heat shock protein 70 prevents both tau aggregation and the inhibitory effects of preexisting tau aggregates on fast axonal transport. Biochemistry, 50(47), 10300–10310.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Pratt, W. B., Gestwicki, J. E., Osawa, Y., et al. (2015). Targeting proteostasis through the protein quality control function of the HSP90/HSP70-based chaperone machinery for treatment of adult onset neurodegenerative diseases. Annual Review of Pharmacology and Toxicology, 55, 353–371.CrossRefPubMedGoogle Scholar
  45. Prusiner, S. B. (2001). Shattucklecture – neurodegenerative diseases and prions. The New England Journal of Medicine, 344(20), 1516–1526.CrossRefPubMedGoogle Scholar
  46. Roodveldt, C., Bertoncini, C. W., Andersson, A., et al. (2009). Chaperone proteostasis in Parkinson’s disease: Stabilization of the HSP70/alpha-synuclein complex by Hip. The EMBO Journal, 28(23), 3758–3770.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Sabirzhanov, B., Stoica, B. A., Hanscom, M., et al. (2012). Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis. Journal of Neurochemistry, 123(4), 542–554.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Selmaj, K., Brosnan, C. F., & Raine, C. S. (1991). Immunology. Proceedings of the National Academy of Sciences of the United States of America, 88, 6452–6456.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Shevtsov, M. A., Nikolaev, B. P., Yakovleva, L. Y., et al. (2014). Neurotherapeutic activity of the recombinant heat shock protein HSP70 in a model of focal cerebral ischemia in rats. Drug Design Development and Therapy, 8, 639–650.CrossRefGoogle Scholar
  50. Suhr, S. T., Senut, M. C., Whitelegge, J. P., et al. (2001). Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. The Journal of Cell Biology, 153(2), 283–294.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Tagawa, K., Marubuchi, S., Qi, M. L., et al. (2007). The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. The Journal of Neuroscience, 27(4), 868–880.CrossRefPubMedGoogle Scholar
  52. Talla, V., Porciatti, V., Chiodo, V., et al. (2014). Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. Investigative Ophthalmology & Visual Science, 55(8), 5214–5226.CrossRefGoogle Scholar
  53. Tamguney, G., Giles, K., Glidden, D. V., et al. (2008). Genes contributing to prion pathogenesis. The Journal of General Virology, 89, 1777–1788.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Vonsattel, J. P., & DiFiglia, M. (1998). Huntington disease. Journal of Neuropathology and Experimental Neurology, 57(5), 369–384.CrossRefPubMedGoogle Scholar
  55. Whyte, L. S., Lau, A. A., Hemsley, K. M., et al. (2017). Endo-lysosomal and autophagic dysfunction: A driving factor in Alzheimer’s disease? Neurochemistry, 140(5), 703–717.CrossRefGoogle Scholar
  56. Yon, M. I., Titiz, A. P., Bilen, S., et al. (2016). Elevated interictal serum HSP-70 levels as an indicator of neurodegeneration for chronic migraine. The Journal of the Pakistan Medical Association, 66(6), 677–681.PubMedGoogle Scholar
  57. Zhou, Y., Gu, G., Goodlett, D. R., et al. (2004). Analysis of alpha-synuclein-associated proteins by quantitative proteomics. The Journal of Biological Chemistry, 279(37), 39155–39164.CrossRefPubMedGoogle Scholar
  58. Zoghbi, H. Y., & Orr, H. T. (2000). Glutamine repeats and neurodegeneration. Annual Review of Neuroscience, 23, 217–247.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Pinar Ortan
    • 1
  • Ozden Yildirim Akan
    • 2
  • Ferda Hosgorler
    • 3
  1. 1.Division of NeurologySB University, Izmir Bozyaka Training and Research HospitalAlsancak IzmirTurkey
  2. 2.Division of İnternal MedicineSB University, Izmir Bozyaka Training and Research HospitalBornova IzmirTurkey
  3. 3.Division of PhysiologyDokuz Eylul University Medical FacultyInciralti/IzmirTurkey

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