Heat Shock Proteins and Neuroprotection

  • Midori A. Yenari
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 513)


In response to many metabolic disturbances and injuries including stroke, neurodegenerative disease, epilepsy and trauma, the cell mounts a stress response with induction of a variety of proteins, most notably the 70 kD heat shock protein (Hsp70). The possibility that stress proteins might be neuroprotective was suspected because Hsp70, in particular, was induced to high levels in brain regions that were relatively resistant to injury. Hsp70 expression was also correlated with the phenomenon of induced tolerance. With the availability of transgenic animals and gene transfer, has it become increasingly clear that such heat shock proteins do indeed protect cells from injury. Several reports have now shown that selective overexpression of Hsp70 leads to protection in several different models of nervous system injury. This review will cover these studies, along with potential mechanisms by which Hsp70 might mediate cellular protection.


Heat Shock Protein Cerebral Ischemia Hsp70 Expression Focal Cerebral Ischemia Kainic Acid 
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  1. 1.
    Sharp FR, Massa SM, Swanson RA. Heat-shock protein protection. Trends Neurosci 1999; 22(3):97–99.PubMedCrossRefGoogle Scholar
  2. 2.
    Yenari MA, Giffard RG, Sapolsky RM et al. The neuroprotective potential of heat shock protein 70 (HSP70). Mol Med Today 1999; 5(12):525–531.PubMedCrossRefGoogle Scholar
  3. 3.
    Kiang JG, Tsokos GC. Heat shock protein 70 kDa: Molecular biology, biochemistry, and physiology. Pharmacol Ther 1998; 80(2):183–201.PubMedCrossRefGoogle Scholar
  4. 4.
    Massa SM, Swanson RA, Sharp FR. The stress gene response in brain. Cerebrovasc Brain Metab Rev 1996; 8(2):95–158.PubMedGoogle Scholar
  5. 5.
    Freeman BC, Myers MP, Schumacher R et al. Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ-1. Embo J 1995; 14(10):2281–2292.PubMedGoogle Scholar
  6. 6.
    Foster JA, Brown IR. Differential induction of heat shock mRNA in oligodendrocytes, microglia, and astrocytes following hyperthermia. Brain Res Mol Brain Res 1997; 45(2):207–128.PubMedCrossRefGoogle Scholar
  7. 7.
    Vass K, Welch WJ, Nowak TS, Jr. Localization of 70-kDa stress protein induction in gerbil brain after ischemia. Acta Neuropathol (Berl) 1988; 77(2):128–135.Google Scholar
  8. 8.
    Kinouchi H, Sharp FR, Hill MP et al. Induction of 70-kDa heat shock protein and Hsp70 mRNA following transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1993; 13(1):105–115.PubMedCrossRefGoogle Scholar
  9. 9.
    Soriano MA, Planas AM, Rodriguez-Farre E et al. Early 72-kDa heat shock protein induction in microglial cells following focal ischemia in the rat brain. Neurosci Lett 1994; 182(2):205–207.PubMedCrossRefGoogle Scholar
  10. 10.
    Nowak TS, Jr., Jacewicz M. The heat shock/stress response in focal cerebral ischemia. Brain Pathol 1994; 4(1):67–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Armstrong JN, Plumier JCL, Robertson HA et al. The inducible 70,000 molecular/weight heat shock protein is expressed in the degenerating dentate hilus and piriform cortex after systemic administration of kainic acid in the rat. Neuroscience 1996; 74(3):685–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang X, Boulton AA, Yu PH. Expression of heat shock protein-70 and limbic seizure-induced neuronal death in the rat brain. Eur J Neurosci 1996; 8:1432–1440.PubMedCrossRefGoogle Scholar
  13. 13.
    Sharp FR. Stress proteins are sensitive indicators of injury in the brain produced by ischemia and toxins. J Toxicol Sci 1995; 20(4):450–453.PubMedGoogle Scholar
  14. 14.
    Gass P, Prior P, Kiessling M. Correlation between seizure intensity and stress protein expression after limbic epilepsy in the rat brain. Neuroscience 1995; 65(1):27–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Chopp M, Li Y, Dereski MO et al. Neuronal injury and expression of 72-kDa heat-shock protein after forebrain ischemia in the rat. Acta Neuropathol (Berl) 1991; 83(1):66–71.CrossRefGoogle Scholar
  16. 16.
    Yang YL, Lin MT. Heat shock protein expression protects against cerebral ischemia and monoamine overload in rat heatstroke. Am J Physiol 1999; 276(6 Pt 2):H1961–H1967.PubMedGoogle Scholar
  17. 17.
    Parsell DA, Lindquist S. Heat shock proteins and stress tolerance. In: Morimoto RI, Tissieres A, Georgopoulos C, eds. The Biology of Heat shock proteins and Molecular Chaperones. New York: Cold Spring Harbor Laboratory Press, 1994:457–494.Google Scholar
  18. 18.
    Yang YL, Lu KT, Tsay HI et al. Heat shock protein expression protects against death following exposure to heatstroke in rats. Neurosci Lett 1998; 252(1):9–12.PubMedCrossRefGoogle Scholar
  19. 19.
    Currie RW, Ellison JA, White RF et al. Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27. Brain Res 2000; 863(12):169–181.PubMedCrossRefGoogle Scholar
  20. 20.
    Bader SB, Price BD, Mannheim-Rodman LA et al. Inhibition of heat shock gene expression does not block the development of thermotolerance. J Cell Phys 1992; 151:56–62.CrossRefGoogle Scholar
  21. 21.
    Mosser DD, Caron AW, Bourget L et al. Role of the human heat shock protein Hsp70 in protection against stress-induced apoptosis. Molec Cellular Biol 1997; 17(9):5317–5327.Google Scholar
  22. 22.
    Hellmann K, Jaattela M, Wissing D et al. Heat shock protein Hsp70 overexpression confers resistance against nitric oxide. FEBS Lett 1996; 391(1–2):185–188.CrossRefGoogle Scholar
  23. 23.
    Jaattela M, Wissing D, Kokholm K et al. Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. Embo J 1998; 17(21):6124–6134.PubMedCrossRefGoogle Scholar
  24. 24.
    Buzzard KA, Giaccia AJ, Killender M et al. Heat shock protein 72 modulates pathways of stress-induced apoptosis. J Biol Chem 1998; 273(27):17147–17153.PubMedCrossRefGoogle Scholar
  25. 25.
    Mestril R, Chi SH, Sayen MR et al. Expression of inducible stress protein 70 in rat heart myogenic cells confers protection against simulated ischemia-induced injury. J Clin Invest 1994; 93(2):759–767.PubMedCrossRefGoogle Scholar
  26. 26.
    Williams RS, Thomas JA, Fina M et al. Human heat shock protein 70 (Hsp70) protects murine cells from injury during metabolic stress. J Clin Invest 1993; 92(I):503–508.PubMedCrossRefGoogle Scholar
  27. 27.
    Beaucamp N, Harding TC, Geddes BJ et al. Overexpression of Hsp70i facilitates reactivation of intracellular proteins in neurones and protects them from denaturing stress. FEBS Lett 1998; 441(2):215–219.PubMedCrossRefGoogle Scholar
  28. 28.
    Fink SL, Chang LK, Ho DY et al. Defective herpes simplex virus vectors expressing the rat brain stress-inducible heat shock protein 72 protect cultured neurons from severe heat shock. J Neurochem (1997); 68(3):961–969.PubMedCrossRefGoogle Scholar
  29. 29.
    Uney JB, Kew IN, Staley K et al. Transfection-mediated expression of human Hsp70i protects rat dorsal root ganglian neurones and glia from severe heat stress. FEBS Lett 1993; 334(3):313–316.PubMedCrossRefGoogle Scholar
  30. 30.
    Uney JB, Staley K, Tyers P et al. Transfection with Hsp70i protects rat dorsal root ganglia neurones and glia from heat stress. Gene Ther 1994; 1 Suppl 1:S65.PubMedGoogle Scholar
  31. 31.
    Mailhos C, Howard MK, Latchman DS. Heat shock proteins hsp90 and Hsp70 protect neuronal cells from thermal stress but not from programmed cell death. J Neurochem 1994; 63(5):1787–1795.PubMedCrossRefGoogle Scholar
  32. 32.
    Wagstaff MJ, Smith J, Collaco-Moraes Y et al. Delivery of a constitutively active form of the heat shock factor using a virus vector protects neuronal cells from thermal or ischaemic stress but not from apoptosis. Eur J Neurosci 1998; 10(11):3343–3350.PubMedCrossRefGoogle Scholar
  33. 33.
    Sato K, Saito H, Matsuki N. HSP70 is essential to the neuroprotective effect of heat-shock. Brain Res 1996; 740(1–2):117–123.PubMedCrossRefGoogle Scholar
  34. 34.
    Plumier JC, Ross BM, Currie RW et al. Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J Clin Invest 1995; 95(4):1854–1860.PubMedCrossRefGoogle Scholar
  35. 35.
    Radford NB, Fina M, Benjamin IJ et al. Cardioprotective effects of 70-kDa heat shock protein in transgenic mice. Proc Natl Acad Sci USA 1996; 93(6):2339–2342.PubMedCrossRefGoogle Scholar
  36. 36.
    Marber MS, Mestril R, Chi SH et al. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 1995; 95(4):1446–1456.PubMedCrossRefGoogle Scholar
  37. 37.
    Wagstaff MJ, Collaco-Moraes Y, Smith J et al. Protection of neuronal cells from apoptosis by Hsp27 delivered with a herpes simplex virus-based vector. J Biol Chem 1999; 274(8):5061–5069.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee J, Yenari M, Sun G et al. Differential neuroprotection from human heat shock protein 70 overexpression in in vitro and in vivo models of ischemia and ischemia-like conditions. Exp Neurol 2001; 170(1):129–139.PubMedCrossRefGoogle Scholar
  39. 39.
    Nishimura RN, Dwyer BE. Evidence for different mechanisms of induction of HSP70i: A comparison of cultured rat cortical neurons with astrocytes. Brain Res Mol Brain Res 1996; 36(2):227–239.PubMedCrossRefGoogle Scholar
  40. 40.
    Papadopoulos MC, Sun XY, Cao J et al. Over-expression of HSP-70 protects against combined oxygen-glucose deprivation. Neuroreport 1996; 7(2):429–432.PubMedCrossRefGoogle Scholar
  41. 41.
    Xu L, Giffard RG. HSP70 protects murine astrocytes from glucose deprivation injury. Neuroscience Letters 1997; 224(1):9–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Rajdev S, Hara K, Kokubo Y et al. Mice overexpressing rat heat shock protein 70 are protected against cerebral infarction. Ann Neurol 2000; 47(6):782–791.PubMedCrossRefGoogle Scholar
  43. 43.
    Plumier JC, Krueger AM, Currie RW et al. Transgenic mice expressing the human inducible Hsp70 have hippocampal neurons resistant to ischemic injury. Cell Stress Chaperones 1997; 2(3):162–167.PubMedCrossRefGoogle Scholar
  44. 44.
    Yenari MA, Minami M, Sun GH et al. Calbindin d28k overexpression protects striatal neurons from transient focal cerebral ischemia. Stroke 2001; 32(4):1028–1035.PubMedCrossRefGoogle Scholar
  45. 45.
    Yenari M, Dumas T, Sapolsky R et al. Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors. Neurol Res 2001; 23:543–552.PubMedCrossRefGoogle Scholar
  46. 46.
    Yenari M, Dumas T, Sapolsky R et al. Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors. In: Slikker W, Trembly B, eds. Neuroprotective Agents: 5th International Conference, Ann NY Acad Sci. Vol. 939. New York: New York Academy of Sciences, 2001:340–357.Google Scholar
  47. 47.
    Yenari MA, Dumas T, Sapolsky RM et al. The role of gene therapy in acute cerebral ischemia. In: Krieglstein K, S. Klumpp, eds. Pharmacology of Cerebral ischemia. Stuttgart: Medpharm Scientific Publishers, 2000:457–472.Google Scholar
  48. 48.
    Yenari MA, Fink SL, Sun GH et al. Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 1998; 44(4):584–591.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang Z, Kelly S, Sun GH et al. HSP72 gene transfer protects CAI neurons from global cerebral ischemia by improving Bcl-2 expression. Soc Neurosci Abs 2001; 27:20.11.Google Scholar
  50. 50.
    Kelly S, Uney JB, McCulloch J. Adenovirus HSP70 gene transfer ameliorate damage following global ischaemia. J Cereb Blood Flow Metab 2001; 21(1):S23.Google Scholar
  51. 51.
    Cummings CJ, Mancini MA, Antalffy B et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998; 19(2):148–154.PubMedCrossRefGoogle Scholar
  52. 52.
    Chai Y, Koppenhafer SL, Bonini NM et al. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci 1999; 19(23):10338–10347.PubMedGoogle Scholar
  53. 53.
    Kobayashi Y, Kume A, Li M et al. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem 2000; 275(12):8772–8778.PubMedCrossRefGoogle Scholar
  54. 54.
    Stenoien DL, Cummings CJ, Adams HP et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet 1999; 8(5):731–741.PubMedCrossRefGoogle Scholar
  55. 55.
    Muchowski PJ, Schaffar G, Sittler A et al. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA 2000; 97(14):7841–7846.PubMedCrossRefGoogle Scholar
  56. 56.
    Cummings CJ, Sun Y, Opal P et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 2001; 10(14):1511–1518.PubMedCrossRefGoogle Scholar
  57. 57.
    Hoehn B, Ringer T, Fink S et al. Postischemic overexpression of HSP72 by gene therapy protects striatal neurons after experimental stroke. J Cereb Blood Flow Metab 2001; 21(suppl. 1):S410.Google Scholar
  58. 58.
    NeckersL Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: Its molecular target and biochemical activity. Invest New Drugs 1999; 17(4):361–373.PubMedCrossRefGoogle Scholar
  59. 59.
    Zou J, Guo Y, Guettouche T et al. Repression of heat shock transcription factor HSF1 activation by HSP90 (1HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 1998; 94(4):471–480.PubMedCrossRefGoogle Scholar
  60. 60.
    Lu A, Nee A, Parmentier S et al. Geldanamycin, a HSP90 binding drug, induces heat shock proteins in vivo and in vitro, and protects against in vivo cerebral ischemia. J Cereb Blood Flow Metab 2001; 21(1):S231.Google Scholar
  61. 61.
    Xiao N, Callaway CW, Lipinski CA et al. Geldanamycin provides posttreatment protection against glutamate-induced oxidative toxicity in a mouse hippocampal cell line. J Neurochem 1999; 72(1):95–101.PubMedCrossRefGoogle Scholar
  62. 62.
    Hu BR, Janelidze S, Ginsberg MD et al. Protein aggregation after focal brain ischemia and reperfusion. J Cereb Blood Flow Metab 2001; 21(7):865–875.PubMedCrossRefGoogle Scholar
  63. 63.
    Hu BR, Martone ME, Jones YZ et al. Protein aggregation after transient cerebral ischemia. J Neurosci 2000; 20(9):3191–3199.PubMedGoogle Scholar
  64. 64.
    Polla BS, Kantengwa S, Francois D et al. Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. Proc Natl Acad Sci USA 1996; 93(13):6458–6463.PubMedCrossRefGoogle Scholar
  65. 65.
    Kamii H, Kinouchi H, Sharp FR et al. Prolonged expression of Hsp70 mRNA following transient focal cerebral ischemia in transgenic mice overexpressing CuZn-superoxide dismutase. J Cereb Blood Flow Metab 1994; 14(3):478–486.PubMedCrossRefGoogle Scholar
  66. 66.
    Kondo T, Murakami K, Honkaniemi J et al. Expression of Hsp70 mRNA is induced in the brain of transgenic mice overexpressing human CuZn-superoxide dismutase following transient global cerebral ischemia. Brain Res 1996; 737(1–2):321–326.PubMedCrossRefGoogle Scholar
  67. 67.
    Kondo T, Sharp FR, Honkaniemi J et al. DNA fragmentation and Prolonged expression of c-fos, c-jun, and Hsp70 in kainic acid-induced neuronal cell death in transgenic mice overexpressing human CuZn-superoxide dismutase. J Cereb Blood Flow Metab 1997; 17(3):241–256.PubMedCrossRefGoogle Scholar
  68. 68.
    Feinstein DL, Galea E, Reis DJ. Suppression of glial nitric oxide synthase induction by heat shock: effects on proteolytic degradation of IkappaB-alpha. Nitric oxide 1997; 1(2):167–176.PubMedCrossRefGoogle Scholar
  69. 69.
    Guzhova IV, Darieva ZA, Melo AR et al. Major stress protein Hsp70 interacts with NF-icB regulatory complex in human T-lymphoma cells. Cell Stress Chaperones 1997; 2(2):132–139.PubMedCrossRefGoogle Scholar
  70. 70.
    Heneka MT, Sharp A, Klockgether T et al. The heat shock response inhibits NF-kappaB activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain. J Cereb Blood Flow Metab 2000; 20(5):800–811.PubMedCrossRefGoogle Scholar
  71. 71.
    Silver PA. How proteins enter the nucleus, Cell 1991; 64(3):489–497.PubMedCrossRefGoogle Scholar
  72. 72.
    Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281(5381):1305–1308.PubMedCrossRefGoogle Scholar
  73. 73.
    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281(5381):1309–1312.PubMedCrossRefGoogle Scholar
  74. 74.
    Gabai VL, Meriin AB, Mosser DD et al. Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 1997; 272(29):18033–18037.PubMedCrossRefGoogle Scholar
  75. 75.
    Gabai VL, Meriin AB, Yaglom JA et al. Role of Hsp70 in regulation of stress-kinase INK: implications in apoptosis and aging. FEBS Lett 1998; 438(1–2):1–4.PubMedCrossRefGoogle Scholar
  76. 76.
    Saleh A, Srinivasula SM, Balkir L et al. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2(8):476–483.PubMedCrossRefGoogle Scholar
  77. 77.
    Beere HM, Wolf BB, Cain K et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000; 2(8):469–475.PubMedCrossRefGoogle Scholar
  78. 78.
    Beere HM, Green DR. Stress management Heat shock protein-70 and the regulation of apoptosis. Trends Cell Biol 2001; 11(1):6–10.PubMedCrossRefGoogle Scholar
  79. 79.
    Creagh EM, Cotter TG. Selective protection by hsp 70 against cytotoxic drug-, but not Fas-induced T-cell apoptosis. Immunology 1999; 97 (1):36–44.PubMedCrossRefGoogle Scholar
  80. 80.
    States BA, Honkaniemi J, Weinstein PR et al. DNA fragmentation and HSP70 protein induction in hippocampus and cortex occurs in separate neurons following permanent middle cerebral artery occlusions. J Cereb Blood Flow Metab 1996; 16 (6):1165–1175.PubMedCrossRefGoogle Scholar
  81. 81.
    Panahian N, Yoshiura M, Maims MD. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J Neurochem 1999; 72(3):1187–1203.PubMedCrossRefGoogle Scholar
  82. 82.
    Yu Z, Luo H, Fu W et al. The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp Neurol 1999; 155 (2):302–314.PubMedCrossRefGoogle Scholar
  83. 83.
    Creagh EM, Carmody RJ, Cotter TG. Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells. Exp Cell Res 2000; 257 (1):58–66.PubMedCrossRefGoogle Scholar
  84. 84.
    Wyatt S, Mailhos C, Latchman DS. Trigeminal ganglion neurons are protected by the heat shock proteins Hsp70 and hsp90 from thermal stress but not from programmed cell death following nerve growth factor withdrawal. Brain Res Mol Brain Res 1996; 39 (1–2):52–56.PubMedCrossRefGoogle Scholar
  85. 85.
    Li GC, Li L, Liu RY et al. Heat shock protein Hsp70 protects cells from thermal stress even after deletion of its ATP-binding domain. Proc Nati Acad Sci USA 1992; 89 (6):2036–2040.CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Midori A. Yenari
    • 1
  1. 1.Department of NeurosurgeryStanford University

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