Journal of Cell Communication and Signaling

, Volume 8, Issue 4, pp 293–310 | Cite as

Heat shock proteins in neurodegenerative disorders and aging

Review

Abstract

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer’s and Parkinson’s disease.

Keywords

Chaperone Vitagene Proteostasis Ageing Aging Adaptation Hormesis 

Abbreviations

ARE

Antioxidant response element

AIF

Apoptosis-inducing factor

Apaf1

Apoptotic protease activation factor 1

Ask1

Apoptosis signal-regulating kinase

ATF6

Activating transcription factor 6

BAG-1

Bcl-2-associated athanogene

CHIP

Carboxy terminus of Hsp70-interacting protein

CHOP

CCAAT-enhancer-binding protein homologous protein

JNK

c-Jun N-terminal kinase

ERAD

Endoplasmic reticulum-associated protein degradation

GRP

Glucose-regulated protein

Hsc70

Heat shock cognate 70

Hsp

Heat shock protein

HO1

Heme oxygenase 1

Hip

Hsp70-interacting protein

Hop

Hsp70/90-organizing protein

Keap1

Kelch-like ECH-associated protein 1

LRRK2

Leucine-rich repeat kinase 2

LAMP2a

Lysosomal-associated membrane transporter 2a

mtHsp70

Mitochondrial Hsp70

Nrf2

Nuclear factor erythroid 2 related factor 2

PERK

PRKR-like endoplasmic reticulum kinase

IRE1

Serine/threonine-protein kinase/endoribonuclease

TPR1

Tetratrico-peptide repeat-1

TRAP1

TNF receptor-associated protein 1

UPR

Unfolded protein response

Notes

Acknowledgments

We apologize that we were not able to include all the many references on heat shock protein expression in the brain. RKL has no conflicts to declare. We are grateful to Mary Caruso, Deb Willson, and Jackie Farrer for outstanding administrative support.

References

  1. Acunzo J, Katsogiannou M, Rocchi P (2012) Small heat shock proteins HSP27 (HspB1), alphaB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. Int J Biochem Cell Biol 44:1622–31PubMedGoogle Scholar
  2. Alladi PA, Mahadevan A, Vijayalakshmi K, Muthane U, Shankar SK, Raju TR (2010) Ageing enhances alpha-synuclein, ubiquitin and endoplasmic reticular stress protein expression in the nigral neurons of Asian Indians. Neurochem Int 57:530–9PubMedGoogle Scholar
  3. Allen NJ, Barres BA (2009) Neuroscience: Glia - more than just brain glue. Nature 457:675–7PubMedGoogle Scholar
  4. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, Schapira AH (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67:1464–72PubMedGoogle Scholar
  5. Angot E, Steiner JA, Hansen C, Li JY, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–38PubMedGoogle Scholar
  6. Arias E, Cuervo AM (2011) Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol 23:184–9PubMedCentralPubMedGoogle Scholar
  7. Aridon P, Geraci F, Turturici G, D’Amelio M, Savettieri G, Sconzo G (2011) Protective role of heat shock proteins in Parkinson’s disease. Neurodegener Dis 8:155–68PubMedGoogle Scholar
  8. Arumugam TV, Phillips TM, Cheng A, Morrell CH, Mattson MP, Wan R (2010) Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol 67:41–52PubMedCentralPubMedGoogle Scholar
  9. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–8PubMedGoogle Scholar
  10. Aztatzi-Santillan E, Nares-Lopez FE, Marquez-Valadez B, Aguilera P, Chanez-Cardenas ME (2010) The protective role of heme oxygenase-1 in cerebral ischemia. Cent Nerv Syst Agents Med Chem 10:310–6PubMedGoogle Scholar
  11. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, Desplats P, Masliah E, Lee SJ (2012) Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci Off J Soc Neurosci 32:13454–69Google Scholar
  12. 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 19:4535–45PubMedCentralPubMedGoogle Scholar
  13. Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–40PubMedGoogle Scholar
  14. Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–75PubMedGoogle Scholar
  15. Blake MJ, Fargnoli J, Gershon D, Holbrook NJ (1991) Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats. Am J Physiol 260:R663–7PubMedGoogle Scholar
  16. Boger HA, Granholm AC, McGinty JF, Middaugh LD (2010) A dual-hit animal model for age-related parkinsonism. Prog Neurobiol 90:217–29PubMedCentralPubMedGoogle Scholar
  17. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–8, discussion 278–84PubMedGoogle Scholar
  18. Braak H, Braak E (1997a) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–8PubMedGoogle Scholar
  19. Braak H, Braak E (1997b) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–7PubMedGoogle Scholar
  20. Braak H, Del Tredici K, Sandmann-Kiel D, Rub U, Schultz C (2001) Nerve cells expressing heat-shock proteins in Parkinson’s disease. Acta Neuropathol (Berl) 102:449–54Google Scholar
  21. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedGoogle Scholar
  22. Brocchieri L, de Macario EC, Macario AJ (2008) hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol 8:19PubMedCentralPubMedGoogle Scholar
  23. Brown MK, Naidoo N (2012) The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 3:263PubMedCentralPubMedGoogle Scholar
  24. Brunner M, Schneider HC, Lill R, Neupert W (1995) Dissection of protein translocation across the mitochondrial outer and inner membranes. Cold Spring Harb Symp Quant Biol 60:619–27PubMedGoogle Scholar
  25. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92:351–66PubMedGoogle Scholar
  26. Burbulla LF, Schelling C, Kato H, Rapaport D, Woitalla D, Schiesling C, Schulte C, Sharma M, Illig T, Bauer P, Jung S, Nordheim A, Schols L, Riess O, Kruger R (2010) Dissecting the role of the mitochondrial chaperone mortalin in Parkinson’s disease: functional impact of disease-related variants on mitochondrial homeostasis. Hum Mol Genet 19:4437–52PubMedCentralPubMedGoogle Scholar
  27. Butler EK, Voigt A, Lutz AK, Toegel JP, Gerhardt E, Karsten P, Falkenburger B, Reinartz A, Winklhofer KF, Schulz JB (2012) The mitochondrial chaperone protein TRAP1 mitigates alpha-Synuclein toxicity. PLoS Genet 8:e1002488PubMedCentralPubMedGoogle Scholar
  28. Calabrese EJ (2010) Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol 29:249–61PubMedGoogle Scholar
  29. Calabrese EJ (2013) Biphasic dose responses in biology, toxicology and medicine: accounting for their generalizability and quantitative features. Environ Pollut 182:452–60PubMedGoogle Scholar
  30. Calabrese EJ, Blain RB (2011) The hormesis database: the occurrence of hormetic dose responses in the toxicological literature. Regul Toxicol Pharmacol: RTP 61:73–81PubMedGoogle Scholar
  31. Calabrese V, Scapagnini G, Ravagna A, Colombrita C, Spadaro F, Butterfield DA, Giuffrida Stella AM (2004) Increased expression of heat shock proteins in rat brain during aging: relationship with mitochondrial function and glutathione redox state. Mech Ageing Dev 125:325–35PubMedGoogle Scholar
  32. Calabrese V, Cornelius C, Mancuso C, Barone E, Calafato S, Bates T, Rizzarelli E, Kostova AT (2009) Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases. Front Biosci 14:376–97Google Scholar
  33. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP (2010) Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 13:1763–811PubMedCentralPubMedGoogle Scholar
  34. Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ (2011) Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Me 32:279–304Google Scholar
  35. Calabrese V, Cornelius C, Dinkova-Kostova AT, Iavicoli I, Di Paola R, Koverech A, Cuzzocrea S, Rizzarelli E, Calabrese EJ (2012) Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 1822:753–83PubMedGoogle Scholar
  36. Cande C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G (2002) Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 84:215–22PubMedGoogle Scholar
  37. Carvey PM, Punati A, Newman MB (2006) Progressive dopamine neuron loss in Parkinson’s disease: the multiple hit hypothesis. Cell Transplant 15:239–50PubMedGoogle Scholar
  38. Cecarini V, Ding Q, Keller JN (2007) Oxidative inactivation of the proteasome in Alzheimer’s disease. Free Radic Res 41:673–80PubMedGoogle Scholar
  39. Chen S, Brown IR (2007) Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases. Cell Stress Chaperones 12:51–8PubMedCentralPubMedGoogle Scholar
  40. Chen CM, Wu YR, Hu FJ, Chen YC, Chuang TJ, Cheng YF, Lee-Chen GJ (2008) HSPA5 promoter polymorphisms and risk of Parkinson’s disease in Taiwan. Neurosci Lett 435:219–22PubMedGoogle Scholar
  41. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35:385–98PubMedGoogle Scholar
  42. Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509:282–3PubMedGoogle Scholar
  43. Conconi M, Friguet B (1997) Proteasome inactivation upon aging and on oxidation-effect of HSP 90. Mol Biol Rep 24:45–50PubMedGoogle Scholar
  44. 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 331:232–40PubMedGoogle Scholar
  45. Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J, Patterson C (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3:93–6PubMedGoogle Scholar
  46. Cornelius C, Perrotta R, Graziano A, Calabrese EJ, Calabrese V (2013) Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”. Immun Ageing: I & A 10:15Google Scholar
  47. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–7PubMedGoogle Scholar
  48. Cuervo AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet: TIG 24:604–12PubMedCentralPubMedGoogle Scholar
  49. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A (2005) Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1:131–40PubMedGoogle Scholar
  50. Dabir DV, Trojanowski JQ, Richter-Landsberg C, Lee VM, Forman MS (2004) Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. Am J Pathol 164:155–66PubMedCentralPubMedGoogle Scholar
  51. Danzer KM, Krebs SK, Wolff M, Birk G, Hengerer B (2009) Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem 111:192–203PubMedGoogle Scholar
  52. Dasuri K, Zhang L, Ebenezer P, Liu Y, Fernandez-Kim SO, Keller JN (2009) Aging and dietary restriction alter proteasome biogenesis and composition in the brain and liver. Mech Ageing Dev 130:777–83PubMedCentralPubMedGoogle Scholar
  53. Dasuri K, Zhang L, Keller JN (2013) Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med 62:170–85PubMedGoogle Scholar
  54. Daturpalli S, Waudby CA, Meehan S, Jackson SE (2013) Hsp90 inhibits alpha-synuclein aggregation by interacting with soluble oligomers. J Mol Biol 425:4614–28PubMedGoogle Scholar
  55. Daugaard M, Rohde M, Jaattela M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–10PubMedGoogle Scholar
  56. De Mena L, Coto E, Sanchez-Ferrero E, Ribacoba R, Guisasola LM, Salvador C, Blazquez M, Alvarez V (2009) Mutational screening of the mortalin gene (HSPA9) in Parkinson’s disease. J Neural Transm 116:1289–93PubMedGoogle Scholar
  57. Dennery PA (2000) Regulation and role of heme oxygenase in oxidative injury. Curr Top Cell Regul 36:181–99PubMedGoogle Scholar
  58. Desmard M, Boczkowski J, Poderoso J, Motterlini R (2007) Mitochondrial and cellular heme-dependent proteins as targets for the bioactive function of the heme oxygenase/carbon monoxide system. Antioxid Redox Signal 9:2139–55PubMedGoogle Scholar
  59. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 106:13010–5PubMedCentralPubMedGoogle Scholar
  60. Di Domenico F, Sultana R, Tiu GF, Scheff NN, Perluigi M, Cini C, Butterfield DA (2010) Protein levels of heat shock proteins 27, 32, 60, 70, 90 and thioredoxin-1 in amnestic mild cognitive impairment: an investigation on the role of cellular stress response in the progression of Alzheimer disease. Brain Res Protocol 1333:72–81Google Scholar
  61. Dickey C, Kraft C, Jinwal U, Koren J, Johnson A, Anderson L, Lebson L, Lee D, Dickson D, de Silva R, Binder LI, Morgan D, Lewis J (2009) Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy. Am J Pathol 174:228–38PubMedCentralPubMedGoogle Scholar
  62. Dickson DW (2009) Neuropathology of non-Alzheimer degenerative disorders. Int J Clin Exp Pathol 3:1–23PubMedGoogle Scholar
  63. Ding X, Goldberg MS (2009) Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP. PLoS One 4:e5949PubMedCentralPubMedGoogle Scholar
  64. Ding Q, Dimayuga E, Keller JN (2006) Proteasome regulation of oxidative stress in aging and age-related diseases of the CNS. Antioxid Redox Signal 8:163–72PubMedGoogle Scholar
  65. Dobson CM (2003) Protein folding and misfolding. Nature 426:884–90PubMedGoogle Scholar
  66. Dong Z, Wolfer DP, Lipp HP, Bueler H (2005) Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther: J Am Soc Gene Ther 11:80–8Google Scholar
  67. Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H (2003) Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A 100:721–6PubMedCentralPubMedGoogle Scholar
  68. Durrenberger PF, Filiou MD, Moran LB, Michael GJ, Novoselov S, Cheetham ME, Clark P, Pearce RK, Graeber MB (2009) DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res 87:238–45PubMedGoogle Scholar
  69. Elliott E, Tsvetkov P, Ginzburg I (2007) BAG-1 associates with Hsc70. Tau complex and regulates the proteasomal degradation of Tau protein. J Biol Chem 282:37276–84PubMedGoogle Scholar
  70. Esser C, Alberti S, Hohfeld J (2004) Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta 1695:171–88PubMedGoogle Scholar
  71. Evans CG, Wisen S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1–42) aggregation in vitro. J Biol Chem 281:33182–91PubMedGoogle Scholar
  72. 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 alpha-synuclein. J Biol Chem 284:31190–9PubMedCentralPubMedGoogle Scholar
  73. Freimann K, Zschiedrich K, Bruggemann N, Grunewald A, Pawlack H, Hagenah J, Lohmann K, Klein C, Westenberger A (2013) Mortalin mutations are not a frequent cause of early-onset Parkinson disease. Neurobiol Aging 34(2694):e19–20PubMedGoogle Scholar
  74. Friguet B, Bulteau AL, Chondrogianni N, Conconi M, Petropoulos I (2000) Protein degradation by the proteasome and its implications in aging. Ann N Y Acad Sci 908:143–54PubMedGoogle Scholar
  75. Gabai VL, Yaglom JA, Volloch V, Meriin AB, Force T, Koutroumanis M, Massie B, Mosser DD, Sherman MY (2000) Hsp72-mediated suppression of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death. Mol Cell Biol 20:6826–36PubMedCentralPubMedGoogle Scholar
  76. Gao HM, Hong JS (2011) Gene-environment interactions: key to unraveling the mystery of Parkinson’s disease. Prog Neurobiol 94:1–19PubMedCentralPubMedGoogle Scholar
  77. Getchell TV, Krishna NS, Dhooper N, Sparks DL, Getchell ML (1995) Human olfactory receptor neurons express heat shock protein 70: age-related trends. Ann Otol Rhinol Laryngol 104:47–56PubMedGoogle Scholar
  78. Gezen-Ak D, Dursun E, Hanagasi H, Bilgic B, Lohman E, Araz OS, Atasoy IL, Alaylioglu M, Onal B, Gurvit H, Yilmazer S (2013) BDNF, TNFalpha, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimers Dis: JAD 37:185–95PubMedGoogle Scholar
  79. Gleixner AM, Pulugulla SH, Pant DB, Posimo JM, Crum TS, Leak RK (2014) Impact of aging on heat shock protein expression in the substantia nigra and striatum of the female rat. Cell Tissue Res 357:43–54PubMedGoogle Scholar
  80. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–9PubMedGoogle Scholar
  81. Goldberg AL (2007) Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem Soc Trans 35:12–7PubMedGoogle Scholar
  82. Gorbatyuk MS, Shabashvili A, Chen W, Meyers C, Sullivan LF, Salganik M, Lin JH, Lewin AS, Muzyczka N, Gorbatyuk OS (2012) Glucose regulated protein 78 diminishes alpha-synuclein neurotoxicity in a rat model of Parkinson disease. Mol Ther: J Am Soc Gene Ther 20:1327–37Google Scholar
  83. Goswami AV, Samaddar M, Sinha D, Purushotham J, D’Silva P (2012) Enhanced J-protein interaction and compromised protein stability of mtHsp70 variants lead to mitochondrial dysfunction in Parkinson’s disease. Hum Mol Genet 21:3317–32PubMedCentralPubMedGoogle Scholar
  84. Grochot-Przeczek A, Dulak J, Jozkowicz A (2012) Haem oxygenase-1: non-canonical roles in physiology and pathology. Clin Sci 122:93–103PubMedGoogle Scholar
  85. Gupte AA, Morris JK, Zhang H, Bomhoff GL, Geiger PC, Stanford JA (2010) Age-related changes in HSP25 expression in basal ganglia and cortex of F344/BN rats. Neurosci Lett 472:90–3PubMedCentralPubMedGoogle Scholar
  86. Hamos JE, Oblas B, Pulaski-Salo D, Welch WJ, Bole DG, Drachman DA (1991) Expression of heat shock proteins in Alzheimer’s disease. Neurology 41:345–50PubMedGoogle Scholar
  87. Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P (2011) alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–25PubMedCentralPubMedGoogle Scholar
  88. Hauser MA, Li YJ, Xu H, Noureddine MA, Shao YS, Gullans SR, Scherzer CR, Jensen RV, McLaurin AC, Gibson JR, Scott BL, Jewett RM, Stenger JE, Schmechel DE, Hulette CM, Vance JM (2005) Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol 62:917–21PubMedGoogle Scholar
  89. Helfert RH, Glatz FR 3rd, Wilson TS, Ramkumar V, Hughes LF (2002) Hsp70 in the inferior colliculus of Fischer-344 rats: effects of age and acoustic stress. Hear Res 170:155–65PubMedGoogle Scholar
  90. Hirose W, Ikematsu K, Tsuda R (2003) Age-associated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Legal Med 5(Suppl 1):S360–6PubMedGoogle Scholar
  91. Hohfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16:6209–16PubMedCentralPubMedGoogle Scholar
  92. Hohfeld J, Minami Y, Hartl FU (1995) Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Cell 83:589–98PubMedGoogle Scholar
  93. Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110:165–72PubMedGoogle Scholar
  94. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 96:3228–33PubMedCentralPubMedGoogle Scholar
  95. Hurtado-Lorenzo A, Anand VS (2008) Heat shock protein 90 modulates LRRK2 stability: potential implications for Parkinson’s disease treatment. J Neurosci Off J Soc Neurosci 28:6757–9Google Scholar
  96. Hussain SG, Ramaiah KV (2007) Reduced eIF2alpha phosphorylation and increased proapoptotic proteins in aging. Biochem Biophys Res Commun 355:365–70PubMedGoogle Scholar
  97. Imaizumi K, Miyoshi K, Katayama T, Yoneda T, Taniguchi M, Kudo T, Tohyama M (2001) The unfolded protein response and Alzheimer’s disease. Biochim Biophys Acta 1536:85–96PubMedGoogle Scholar
  98. Jazwa A, Cuadrado A (2010) Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. Curr Drug Targets 11:1517–31PubMedGoogle Scholar
  99. Jellinger KA (2008) Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener Dis 5:118–21PubMedGoogle Scholar
  100. Jellinger KA (2009) Recent advances in our understanding of neurodegeneration. J Neural Transm 116:1111–62PubMedGoogle Scholar
  101. Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J, Patterson C (2001) CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276:42938–44PubMedGoogle Scholar
  102. Jin J, Hulette C, Wang Y, Zhang T, Pan C, Wadhwa R, Zhang J (2006) Proteomic identification of a stress protein, mortalin/mthsp70/GRP75: relevance to Parkinson disease. Mol Cell Proteomics: MCP 5:1193–204PubMedGoogle Scholar
  103. Jinwal UK, O’Leary JC 3rd, Borysov SI, Jones JR, Li Q, Koren J 3rd, Abisambra JF, Vestal GD, Lawson LY, Johnson AG, Blair LJ, Jin Y, Miyata Y, Gestwicki JE, Dickey CA (2010) Hsc70 rapidly engages tau after microtubule destabilization. J Biol Chem 285:16798–805PubMedCentralPubMedGoogle Scholar
  104. Johnson JL, Brown C (2009) Plasticity of the Hsp90 chaperone machine in divergent eukaryotic organisms. Cell Stress Chaperones 14:83–94PubMedCentralPubMedGoogle Scholar
  105. Jung AE, Fitzsimons HL, Bland RJ, During MJ, Young D (2008) HSP70 and constitutively active HSF1 mediate protection against CDCrel-1-mediated toxicity. Mol Ther: J Am Soc Gene Ther 16:1048–55Google Scholar
  106. Kabani M, Martineau CN (2008) Multiple hsp70 isoforms in the eukaryotic cytosol: mere redundancy or functional specificity? Curr Genom 9:338–248Google Scholar
  107. Kalia SK, Kalia LV, McLean PJ (2010) Molecular chaperones as rational drug targets for Parkinson’s disease therapeutics. CNS Neurol Disord Drug Targets 9:741–53PubMedCentralPubMedGoogle Scholar
  108. Kalia LV, Kalia SK, Chau H, Lozano AM, Hyman BT, McLean PJ (2011) Ubiquitinylation of alpha-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 6:e14695PubMedCentralPubMedGoogle Scholar
  109. Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1:479–85PubMedGoogle Scholar
  110. Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M (2004) Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 28:67–78PubMedGoogle Scholar
  111. Kaushik S, Cuervo AM (2006) Autophagy as a cell-repair mechanism: activation of chaperone-mediated autophagy during oxidative stress. Mol Aspects Med 27:444–54PubMedCentralPubMedGoogle Scholar
  112. Kaushik S, Cuervo AM (2009) Methods to monitor chaperone-mediated autophagy. Methods Enzymol 452:297–324PubMedGoogle Scholar
  113. Kawamoto Y, Akiguchi I, Shirakashi Y, Honjo Y, Tomimoto H, Takahashi R, Budka H (2007) Accumulation of Hsc70 and Hsp70 in glial cytoplasmic inclusions in patients with multiple system atrophy. Brain Res Protocol 1136:219–27Google Scholar
  114. Keller JN, Hanni KB, Markesbery WR (2000a) Possible involvement of proteasome inhibition in aging: implications for oxidative stress. Mech Ageing Dev 113:61–70PubMedGoogle Scholar
  115. Keller JN, Huang FF, Markesbery WR (2000b) Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience 98:149–56PubMedGoogle Scholar
  116. Keller JN, Gee J, Ding Q (2002) The proteasome in brain aging. Ageing Res Rev 1:279–93PubMedGoogle Scholar
  117. Keller JN, Dimayuga E, Chen Q, Thorpe J, Gee J, Ding Q (2004) Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol 36:2376–91PubMedGoogle Scholar
  118. Kennedy D, Jager R, Mosser DD, Samali A (2014) Regulation of apoptosis by heat shock proteins. IUBMB LifeGoogle Scholar
  119. Kisselev AF, Goldberg AL (2005) Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates. Methods Enzymol 398:364–78PubMedGoogle Scholar
  120. Kisselev AF, Garcia-Calvo M, Overkleeft HS, Peterson E, Pennington MW, Ploegh HL, Thornberry NA, Goldberg AL (2003) The caspase-like sites of proteasomes, their substrate specificity, new inhibitors and substrates, and allosteric interactions with the trypsin-like sites. J Biol Chem 278:35869–77PubMedGoogle Scholar
  121. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–502PubMedGoogle Scholar
  122. Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, Patterson C, Petrucelli L, Dawson TM, Dawson VL (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci U S A 106:2897–902PubMedCentralPubMedGoogle Scholar
  123. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10:205–15PubMedCentralPubMedGoogle Scholar
  124. Kroemer G (2001) Heat shock protein 70 neutralizes apoptosis-inducing factor. Sci World J 1:590–2Google Scholar
  125. Krueger-Naug AM, Plumier JC, Hopkins DA, Currie RW (2002) Hsp27 in the nervous system: expression in pathophysiology and in the aging brain. Prog Mol Subcell Biol 28:235–51PubMedGoogle Scholar
  126. Kumar P, Ambasta RK, Veereshwarayya V, Rosen KM, Kosik KS, Band H, Mestril R, Patterson C, Querfurth HW (2007) CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism. Hum Mol Genet 16:848–64PubMedGoogle Scholar
  127. Labbadia J, Morimoto RI (2014) Proteostasis and longevity: when does aging really begin? F1000 prime reports 6: 7Google Scholar
  128. Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C (2008) Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 12:743–61PubMedGoogle Scholar
  129. Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. Sci World J 10:1543–52Google Scholar
  130. Leak RK (2014) Adaptation and sensitization to proteotoxic stress. Dose–response: Publ Int Hormesis Soc 12:24–56Google Scholar
  131. Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol: JASN 17:1807–19PubMedGoogle Scholar
  132. Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–7PubMedGoogle Scholar
  133. Lee KS, Chung JH, Oh BH, Hong CH (2008) Increased plasma levels of heat shock protein 70 in patients with vascular mild cognitive impairment. Neurosci Lett 436:223–6PubMedGoogle Scholar
  134. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ (2010a) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–72PubMedCentralPubMedGoogle Scholar
  135. Lee JH, Won SM, Suh J, Son SJ, Moon GJ, Park UJ, Gwag BJ (2010b) Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice. Exp Mol Med 42:386–94PubMedCentralPubMedGoogle Scholar
  136. Lee CH, Park JH, Choi JH, Yoo KY, Ryu PD, Won MH (2011) Heat shock protein 90 and its cochaperone, p23, are markedly increased in the aged gerbil hippocampus. Exp Gerontol 46:768–72PubMedGoogle Scholar
  137. Leverenz JB, Umar I, Wang Q, Montine TJ, McMillan PJ, Tsuang DW, Jin J, Pan C, Shin J, Zhu D, Zhang J (2007) Proteomic identification of novel proteins in cortical lewy bodies. Brain Pathol 17:139–45PubMedGoogle Scholar
  138. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–217PubMedCentralPubMedGoogle Scholar
  139. Lowe J, McDermott H, Pike I, Spendlove I, Landon M, Mayer RJ (1992) alpha B crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease. J Pathol 166:61–8PubMedGoogle Scholar
  140. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–91PubMedGoogle Scholar
  141. Luk KC, Mills IP, Trojanowski JQ, Lee VM (2008) Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly. Biochemistry 47:12614–25PubMedCentralPubMedGoogle Scholar
  142. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012a) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–53PubMedCentralPubMedGoogle Scholar
  143. Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012b) Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 209:975–86PubMedCentralPubMedGoogle Scholar
  144. Magrane J, Smith RC, Walsh K, Querfurth HW (2004) Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed beta-amyloid in neurons. J Neurosci Off J Soc Neurosci 24:1700–6Google Scholar
  145. Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MB (2005) Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci 1053:356–75PubMedGoogle Scholar
  146. Manning-Bog AB, Langston JW (2007) Model fusion, the next phase in developing animal models for Parkinson’s disease. Neurotox Res 11:219–40PubMedGoogle Scholar
  147. Massey A, Kiffin R, Cuervo AM (2004) Pathophysiology of chaperone-mediated autophagy. Int J Biochem Cell Biol 36:2420–34PubMedGoogle Scholar
  148. Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73:205–35PubMedGoogle Scholar
  149. Mattson MP (2008) Hormesis defined. Ageing Res Rev 7:1–7PubMedCentralPubMedGoogle Scholar
  150. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci: CMLS 62:670–84PubMedCentralPubMedGoogle Scholar
  151. 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 alpha-synuclein aggregation. J Neurochem 83:846–54PubMedGoogle Scholar
  152. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2006) Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281:24756–68PubMedGoogle Scholar
  153. Milne KJ, Noble EG (2008) Response of the myocardium to exercise: sex-specific regulation of hsp70. Med Sci Sports Exerc 40:655–63PubMedGoogle Scholar
  154. Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C (2008) CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 28:4018–25PubMedCentralPubMedGoogle Scholar
  155. Minami Y, Hohfeld J, Ohtsuka K, Hartl FU (1996) Regulation of the heat-shock protein 70 reaction cycle by the mammalian DnaJ homolog, Hsp40. J Biol Chem 271:19617–24PubMedGoogle Scholar
  156. Molochnikov L, Rabey JM, Dobronevsky E, Bonucelli U, Ceravolo R, Frosini D, Grunblatt E, Riederer P, Jacob C, Aharon-Peretz J, Bashenko Y, Youdim MB, Mandel SA (2012) A molecular signature in blood identifies early Parkinson’s disease. Mol Neurodegener 7:26PubMedCentralPubMedGoogle Scholar
  157. Morimoto RI (2008) Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22:1427–38PubMedCentralPubMedGoogle Scholar
  158. Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–9PubMedGoogle Scholar
  159. Morimoto RI, Cuervo AM (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A: Biol Med Sci 69(Suppl 1):S33–8Google Scholar
  160. Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22PubMedGoogle Scholar
  161. Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338PubMedCentralPubMedGoogle Scholar
  162. Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB, Yasha TC, Srinivas Bharath MM, Shankar SK (2011) Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson’s disease brains. Neurochem Res 36:1452–63PubMedGoogle Scholar
  163. Nagel F, Falkenburger BH, Tonges L, Kowsky S, Poppelmeyer C, Schulz JB, Bahr M, Dietz GP (2008) Tat-Hsp70 protects dopaminergic neurons in midbrain cultures and in the substantia nigra in models of Parkinson’s disease. J Neurochem 105:853–64PubMedGoogle Scholar
  164. Naidoo N, Ferber M, Master M, Zhu Y, Pack AI (2008) Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci Off J Soc Neurosci 28:6539–48Google Scholar
  165. Njemini R, Lambert M, Demanet C, Kooijman R, Mets T (2007) Basal and infection-induced levels of heat shock proteins in human aging. Biogerontology 8:353–64PubMedGoogle Scholar
  166. Nowotny K, Jung T, Grune T, Hohn A (2014) Accumulation of modified proteins and aggregate formation in aging. Exp Gerontol 57:122–131PubMedGoogle Scholar
  167. Orenstein SJ, Cuervo AM (2010) Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 21:719–26PubMedCentralPubMedGoogle Scholar
  168. Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet JC, Hyman BT, McLean PJ (2006) Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. Biochem Biophys Res Commun 351:631–8PubMedCentralPubMedGoogle Scholar
  169. Pardue S, Groshan K, Raese JD, Morrison-Bogorad M (1992) Hsp70 mRNA induction is reduced in neurons of aged rat hippocampus after thermal stress. Neurobiol Aging 13:661–72PubMedGoogle Scholar
  170. Pardue S, Wang S, Miller MM, Morrison-Bogorad M (2007) Elevated levels of inducible heat shock 70 proteins in human brain. Neurobiol Aging 28:314–24PubMedGoogle Scholar
  171. Park HS, Lee JS, Huh SH, Seo JS, Choi EJ (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20:446–56PubMedCentralPubMedGoogle Scholar
  172. Park HS, Cho SG, Kim CK, Hwang HS, Noh KT, Kim MS, Huh SH, Kim MJ, Ryoo K, Kim EK, Kang WJ, Lee JS, Seo JS, Ko YG, Kim S, Choi EJ (2002) Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1. Mol Cell Biol 22:7721–30PubMedCentralPubMedGoogle Scholar
  173. Paz Gavilan M, Vela J, Castano A, Ramos B, del Rio JC, Vitorica J, Ruano D (2006) Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol Aging 27:973–82PubMedGoogle Scholar
  174. Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–94PubMedGoogle Scholar
  175. Posimo JM, Titler AM, Choi HJ, Unnithan AS, Leak RK (2013) Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo. PLoS One 8:e58596PubMedCentralPubMedGoogle Scholar
  176. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jaattela M, Penninger JM, Garrido C, Kroemer G (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–43PubMedGoogle Scholar
  177. Renkawek K, Bosman GJ, Gaestel M (1993) Increased expression of heat-shock protein 27 kDa in Alzheimer disease: a preliminary study. Neuroreport 5:14–6PubMedGoogle Scholar
  178. Renkawek K, Bosman GJ, de Jong WW (1994a) Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia. Acta Neuropathol 87:511–9PubMedGoogle Scholar
  179. Renkawek K, Voorter CE, Bosman GJ, van Workum FP, de Jong WW (1994b) Expression of alpha B-crystallin in Alzheimer’s disease. Acta Neuropathol 87:155–60PubMedGoogle Scholar
  180. Renkawek K, Stege GJ, Bosman GJ (1999) Dementia, gliosis and expression of the small heat shock proteins hsp27 and alpha B-crystallin in Parkinson’s disease. Neuroreport 10:2273–6PubMedGoogle Scholar
  181. Roodveldt C, Bertoncini CW, Andersson A, van der Goot AT, Hsu ST, Fernandez-Montesinos R, de Jong J, van Ham TJ, Nollen EA, Pozo D, Christodoulou J, Dobson CM (2009) Chaperone proteostasis in Parkinson’s disease: stabilization of the Hsp70/alpha-synuclein complex by Hip. EMBO J 28:3758–70PubMedCentralPubMedGoogle Scholar
  182. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–7PubMedGoogle Scholar
  183. Rudenko IN, Kaganovich A, Hauser DN, Beylina A, Chia R, Ding J, Maric D, Jaffe H, Cookson MR (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson’s disease is a partial loss-of-function mutation. Biochem J 446:99–111PubMedGoogle Scholar
  184. Ryter SW, Tyrrell RM (2000) The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 28:289–309PubMedGoogle Scholar
  185. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–83PubMedGoogle Scholar
  186. Salminen A, Ojala J, Kaarniranta K, Hiltunen M, Soininen H (2011) Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer’s disease. Prog Neurobiol 93:99–110PubMedGoogle Scholar
  187. Salway KD, Gallagher EJ, Page MM, Stuart JA (2011) Higher levels of heat shock proteins in longer-lived mammals and birds. Mech Ageing Dev 132:287–97PubMedGoogle Scholar
  188. Sato N, Urano F, Yoon Leem J, Kim SH, Li M, Donoviel D, Bernstein A, Lee AS, Ron D, Veselits ML, Sisodia SS, Thinakaran G (2000) Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression. Nat Cell Biol 2:863–70PubMedGoogle Scholar
  189. Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci U S A 104:955–60PubMedCentralPubMedGoogle Scholar
  190. 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 101:199–210PubMedGoogle Scholar
  191. Schipper HM (2000) Heme oxygenase-1: role in brain aging and neurodegeneration. Exp Gerontol 35:821–30PubMedGoogle Scholar
  192. Schipper HM (2011) Heme oxygenase-1 in Alzheimer disease: a tribute to Moussa Youdim. J Neural Transm 118:381–7PubMedGoogle Scholar
  193. Schipper HM, Liberman A, Stopa EG (1998) Neural heme oxygenase-1 expression in idiopathic Parkinson’s disease. Exp Neurol 150:60–8PubMedGoogle Scholar
  194. Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27:252–61PubMedGoogle Scholar
  195. Schipper HM, Song W, Zukor H, Hascalovici JR, Zeligman D (2009) Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement. J Neurochem 110:469–85PubMedGoogle Scholar
  196. Schneider HC, Berthold J, Bauer MF, Dietmeier K, Guiard B, Brunner M, Neupert W (1994) Mitochondrial Hsp70/MIM44 complex facilitates protein import. Nature 371:768–74PubMedGoogle Scholar
  197. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63PubMedGoogle Scholar
  198. Schultz C, Dick EJ, Cox AB, Hubbard GB, Braak E, Braak H (2001) Expression of stress proteins alpha B-crystallin, ubiquitin, and hsp27 in pallido-nigral spheroids of aged rhesus monkeys. Neurobiol Aging 22:677–82PubMedGoogle Scholar
  199. Seidel K, Vinet J, Dunnen WF, Brunt ER, Meister M, Boncoraglio A, Zijlstra MP, Boddeke HW, Rub U, Kampinga HH, Carra S (2012) The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases. Neuropathol Appl Neurobiol 38:39–53PubMedGoogle Scholar
  200. Selye H (1975) Stress without distress. Signet, Philadelphia, VolGoogle Scholar
  201. Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32PubMedGoogle Scholar
  202. Shimura H, Schwartz D, Gygi SP, Kosik KS (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–76PubMedGoogle Scholar
  203. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727–34PubMedGoogle Scholar
  204. Shinohara H, Inaguma Y, Goto S, Inagaki T, Kato K (1993) Alpha B crystallin and HSP28 are enhanced in the cerebral cortex of patients with Alzheimer’s disease. J Neurol Sci 119:203–8PubMedGoogle Scholar
  205. Soti C, Csermely P (2000) Molecular chaperones and the aging process. Biogerontology 1:225–33PubMedGoogle Scholar
  206. Stege GJ, Renkawek K, Overkamp PS, Verschuure P, van Rijk AF, Reijnen-Aalbers A, Boelens WC, Bosman GJ, de Jong WW (1999) The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity. Biochem Biophys Res Commun 262:152–6PubMedGoogle Scholar
  207. Sultana R, Boyd-Kimball D, Cai J, Pierce WM, Klein JB, Merchant M, Butterfield DA (2007) Proteomics analysis of the Alzheimer’s disease hippocampal proteome. J Alzheimers Dis: JAD 11:153–64PubMedGoogle Scholar
  208. Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–50PubMedGoogle Scholar
  209. Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, McLean PJ (2008) CHIP targets toxic alpha-Synuclein oligomers for degradation. J Biol Chem 283:17962–8PubMedCentralPubMedGoogle Scholar
  210. Titler AM, Posimo JM, Leak RK (2013) Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. Cell Tissue Res 352:427–43PubMedGoogle Scholar
  211. Tohgi H, Utsugisawa K, Yoshimura M, Yamagata M, Nagane Y (1995) Heat-shock cognate 70 messenger RNA expression in postmortem human hippocampus: regional differences and age-related changes. Neurosci Lett 196:89–92PubMedGoogle Scholar
  212. Toth ME, Szegedi V, Varga E, Juhasz G, Horvath J, Borbely E, Csibrany B, Alfoldi R, Lenart N, Penke B, Santha M (2013) Overexpression of Hsp27 ameliorates symptoms of Alzheimer’s disease in APP/PS1 mice. Cell Stress Chaperones 18:759–71PubMedCentralPubMedGoogle Scholar
  213. Unnithan AS, Choi HJ, Titler AM, Posimo JM, Leak RK (2012) Rescue from a two hit, high-throughput model of neurodegeneration with N-acetyl cysteine. Neurochem Int 61:356–368PubMedGoogle Scholar
  214. Unnithan AS, Jiang Y, Rumble JL, Pulugulla SH, Posimo JM, Gleixner AM, Leak RK (2013) N-acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress. Neurosci Lett 560:71–6PubMedGoogle Scholar
  215. Unno K, Asakura H, Shibuya Y, Kaiho M, Okada S, Oku N (2000) Increase in basal level of Hsp70, consisting chiefly of constitutively expressed Hsp70 (Hsc70) in aged rat brain. J Gerontol A: Biol Med Sci 55:B329–35Google Scholar
  216. Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham CT, Yazawa I, Hilburger K, Micsenyi M, Giasson BI, Bonini NM, Lee VM, Trojanowski JQ (2006) Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 168:947–61PubMedCentralPubMedGoogle Scholar
  217. Uversky VN (2009) Intrinsic disorder in proteins associated with neurodegenerative diseases. Front Biosci: J Virtual Libr 14:5188–238Google Scholar
  218. Viana RJ, Nunes AF, Rodrigues CM (2012) Endoplasmic reticulum enrollment in Alzheimer’s disease. Mol Neurobiol 46:522–34PubMedGoogle Scholar
  219. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71PubMedCentralPubMedGoogle Scholar
  220. Walsh DM, Selkoe DJ (2007) A beta oligomers - a decade of discovery. J Neurochem 101:1172–84PubMedGoogle Scholar
  221. Walters TJ, Ryan KL, Mason PA (2001) Regional distribution of Hsp70 in the CNS of young and old food-restricted rats following hyperthermia. Brain Res Bull 55:367–74PubMedGoogle Scholar
  222. Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L, Chandran J, Lin X, Lai C, Yang WJ, Moore DJ, Dawson TM, Dawson VL, Chiosis G, Cookson MR, Cai H (2008) The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci Off J Soc Neurosci 28:3384–91Google Scholar
  223. Weidong L, Shen C, Jankovic J (2009) Etiopathogenesis of Parkinson disease: a new beginning? Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 15:28–35Google Scholar
  224. Wilhelmus MM, Otte-Holler I, Wesseling P, de Waal RM, Boelens WC, Verbeek MM (2006) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer’s disease brains. Neuropathol Appl Neurobiol 32:119–30PubMedGoogle Scholar
  225. Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2:a006734PubMedCentralPubMedGoogle Scholar
  226. Wu ML, Ho YC, Yet SF (2011) A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal 15:1835–46PubMedGoogle Scholar
  227. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–7PubMedGoogle Scholar
  228. Xilouri M, Stefanis L (2010) Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 9:701–19PubMedGoogle Scholar
  229. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758–70PubMedCentralPubMedGoogle Scholar
  230. Yang Y, Turner RS, Gaut JR (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J Biol Chem 273:25552–5PubMedGoogle Scholar
  231. Yokota T, Mishra M, Akatsu H, Tani Y, Miyauchi T, Yamamoto T, Kosaka K, Nagai Y, Sawada T, Heese K (2006) Brain site-specific gene expression analysis in Alzheimer’s disease patients. Eur J Clin Investig 36:820–30Google Scholar
  232. Yoo BC, Seidl R, Cairns N, Lubec G (1999) Heat-shock protein 70 levels in brain of patients with Down syndrome and Alzheimer’s disease. J Neural Transm Suppl 57:315–22PubMedGoogle Scholar
  233. Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20:588–94PubMedGoogle Scholar
  234. Zhang J, Piantadosi CA (1992) Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 90:1193–9PubMedCentralPubMedGoogle Scholar
  235. Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet: Off Publ Int Soc Psychiatr Genet 137B:5–16Google Scholar
  236. Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47PubMedCentralPubMedGoogle Scholar
  237. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 123:39–46PubMedGoogle Scholar
  238. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772:494–502PubMedGoogle Scholar

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© The International CCN Society 2014

Authors and Affiliations

  1. 1.Division of Pharmaceutical SciencesDuquesne UniversityPittsburghUSA

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