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Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders

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Abstract

Proteome homeostasis, or proteostasis, is essential to maintain cellular fitness and its disturbance is associated with a broad range of human health conditions and diseases. Cells are constantly challenged by various extrinsic and intrinsic insults, which perturb cellular proteostasis and provoke proteotoxic stress. To counter proteomic perturbations and preserve proteostasis, cells mobilize the proteotoxic stress response (PSR), an evolutionarily conserved transcriptional program mediated by heat shock factor 1 (HSF1). The HSF1-mediated PSR guards the proteome against misfolding and aggregation. In addition to proteotoxic stress, emerging studies reveal that this proteostatic mechanism also responds to cellular energy state. This regulation is mediated by the key cellular metabolic sensor AMP-activated protein kinase (AMPK). In this review, we present an overview of the maintenance of proteostasis by HSF1, the metabolic regulation of the PSR, particularly focusing on AMPK, and their implications in the two major age-related diseases—diabetes mellitus and neurodegenerative disorders.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AD:

Alzheimer’s disease

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleoside

AMPK:

AMP-activated protein kinase

APP:

Amyloid precursor protein

AR:

Androgen receptor

AKT:

v-Akt murine thymoma viral oncogene homolog

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CAMKK:

Ca2+/calmodulin-dependent protein kinase kinase β

DM:

Diabetes mellitus

EIF4EBP1:

Eukaryotic translation initiation factor 4E (elF4E)-binding protein 1

ERK:

Extracellular signal-regulated kinase

GSK3β:

Glycogen synthase kinase 3 β

HD:

Huntington disease

HSE:

Heat shock element

HSF:

Heat shock factor

HSP:

Heat shock proteins

HSR:

Heat shock response

IAPP:

Islet amyloid polypeptide

IDE:

Insulin-degrading enzyme

IKKβ:

Inhibitor of nuclear factor kappa-B kinase subunit beta

IR:

Insulin receptor

IRS-1/2:

Insulin receptor substrate-1/2

JNK:

c-Jun N-terminal kinase

LKB1:

Liver kinase B1

mTORC1:

Mammalian target of rapamycin complex 1

MSR:

Metabolic stress response

PDK:

Phosphoinositide-dependent kinase

PGC-1α:

Peroxisome proliferator–activated receptor gamma coactivator 1-alpha

PI3K:

Phosphoinositide 3-kinase

polyQ:

Polyglutamine

PSR:

Proteotoxic stress response

STZ:

Streptozotocin

SUMO:

Small ubiquitin-like modifier

References

  1. Gidalevitz T, Prahlad V, Morimoto RI (2011) The stress of protein misfolding: from single cells to multicellular organisms. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a009704

    PubMed  PubMed Central  Google Scholar 

  2. Lindquist SL, Kelly JW (2011) Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a004507

    PubMed  PubMed Central  Google Scholar 

  3. Fernandes M, Xiao H, Lis JT (1994) Fine structure analyses of the Drosophila and Saccharomyces heat shock factor-heat shock element interactions. Nucleic Acids Res 22(2):167–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pirkkala L, Nykanen P, Sistonen L (2001) Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. Faseb J 15(7):1118–1131

    Article  CAS  PubMed  Google Scholar 

  5. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21(17):5899–5912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Altman BJ, Rathmell JC (2012) Metabolic stress in autophagy and cell death pathways. Cold Spring Harb Perspect Biol 4(9):a008763. doi:10.1101/cshperspect.a008763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Zhao Y, Coloff JL, Ferguson EC, Jacobs SR, Cui K, Rathmell JC (2008) Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. J Biol Chem 283(52):36344–36353. doi:10.1074/jbc.M803580200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324(5930):1076–1080. doi:10.1126/science.1164097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Luo Z, Saha AK, Xiang X, Ruderman NB (2005) AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 26(2):69–76. doi:10.1016/j.tips.2004.12.011

    Article  CAS  PubMed  Google Scholar 

  10. Vucenik I, Stains JP (2012) Obesity and cancer risk: evidence, mechanisms, and recommendations. Ann N Y Acad Sci 1271:37–43. doi:10.1111/j.1749-6632.2012.06750.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carro EM (2009) Therapeutic approaches of leptin in Alzheimer’s disease. Recent Pat CNS Drug Discov 4(3):200–208

    Article  CAS  PubMed  Google Scholar 

  12. Welch WJ (1991) The role of heat-shock proteins as molecular chaperones. Curr Opin Cell Biol 3(6):1033–1038

    Article  CAS  PubMed  Google Scholar 

  13. Iwasaki S, Kobayashi M, Yoda M, Sakaguchi Y, Katsuma S, Suzuki T, Tomari Y (2010) Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes. Mol Cell 39(2):292–299. doi:10.1016/j.molcel.2010.05.015

    Article  CAS  PubMed  Google Scholar 

  14. Kaufman RJ, Back SH, Song B, Han J, Hassler J (2010) The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in beta-cells. Diabetes Obes Metab 12(Suppl 2):99–107. doi:10.1111/j.1463-1326.2010.01281.x

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14(9):1576–1582. doi:10.1038/sj.cdd.4402200

    Article  CAS  PubMed  Google Scholar 

  16. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519–529. doi:10.1038/nrm2199

    Article  CAS  PubMed  Google Scholar 

  17. Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125(3):443–451. doi:10.1016/j.cell.2006.04.014

    Article  CAS  PubMed  Google Scholar 

  18. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295(5561):1852–1858. doi:10.1126/science.1068408

    Article  CAS  PubMed  Google Scholar 

  19. Akerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11(8):545–555. doi:10.1038/nrm2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Anckar J, Sistonen L (2011) Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 80:1089–1115. doi:10.1146/annurev-biochem-060809-095203

    Article  CAS  PubMed  Google Scholar 

  21. Dai C, Dai S, Cao J (2012) Proteotoxic stress of cancer: implication of the heat-shock response in oncogenesis. J Cell Physiol 227(8):2982–2987. doi:10.1002/jcp.24017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fujimoto M, Nakai A (2010) The heat shock factor family and adaptation to proteotoxic stress. FEBS J 277(20):4112–4125

    Article  CAS  PubMed  Google Scholar 

  23. Akerfelt M, Vihervaara A, Laiho A, Conter A, Christians ES, Sistonen L, Henriksson E (2010) Heat shock transcription factor 1 localizes to sex chromatin during meiotic repression. J Biol Chem 285(45):34469–34476. doi:10.1074/jbc.M110.157552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vuister GW, Kim SJ, Orosz A, Marquardt J, Wu C, Bax A (1994) Solution structure of the DNA-binding domain of Drosophila heat shock transcription factor. Nat Struct Biol 1(9):605–614

    Article  CAS  PubMed  Google Scholar 

  25. Littlefield O, Nelson HC (1999) A new use for the ‘wing’ of the ‘winged’ helix-turn-helix motif in the HSF-DNA cocrystal. Nat Struct Biol 6(5):464–470. doi:10.1038/8269

    Article  CAS  PubMed  Google Scholar 

  26. Shi Y, Mosser DD, Morimoto RI (1998) Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev 12(5):654–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rabindran SK, Haroun RI, Clos J, Wisniewski J, Wu C (1993) Regulation of heat shock factor trimer formation: role of a conserved leucine zipper. Science 259(5092):230–234

    Article  CAS  PubMed  Google Scholar 

  28. Peteranderl R, Rabenstein M, Shin YK, Liu CW, Wemmer DE, King DS, Nelson HC (1999) Biochemical and biophysical characterization of the trimerization domain from the heat shock transcription factor. Biochemistry 38(12):3559–3569. doi:10.1021/bi981774j

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Barlev NA, Westergaard O, Jakobsen BK (1993) Identification of the C-terminal activator domain in yeast heat shock factor: independent control of transient and sustained transcriptional activity. EMBO J 12(13):5007–5018

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wisniewski J, Orosz A, Allada R, Wu C (1996) The C-terminal region of Drosophila heat shock factor (HSF) contains a constitutively functional transactivation domain. Nucleic Acids Res 24(2):367–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Newton EM, Knauf U, Green M, Kingston RE (1996) The regulatory domain of human heat shock factor 1 is sufficient to sense heat stress. Mol Cell Biol 16(3):839–846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Green M, Schuetz TJ, Sullivan EK, Kingston RE (1995) A heat shock-responsive domain of human HSF1 that regulates transcription activation domain function. Mol Cell Biol 15(6):3354–3362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guo Y, Guettouche T, Fenna M, Boellmann F, Pratt WB, Toft DO, Smith DF, Voellmy R (2001) Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. J Biol Chem 276(49):45791–45799. doi:10.1074/jbc.M105931200

    Article  CAS  PubMed  Google Scholar 

  34. McMillan DR, Xiao X, Shao L, Graves K, Benjamin IJ (1998) Targeted disruption of heat shock transcription factor 1 abolishes thermotolerance and protection against heat-inducible apoptosis. J Biol Chem 273(13):7523–7528

    Article  CAS  PubMed  Google Scholar 

  35. He H, Soncin F, Grammatikakis N, Li Y, Siganou A, Gong J, Brown SA, Kingston RE, Calderwood SK (2003) Elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during stress. J Biol Chem 278(37):35465–35475. doi:10.1074/jbc.M304663200

    Article  CAS  PubMed  Google Scholar 

  36. Loison F, Debure L, Nizard P, le Goff P, Michel D, le Drean Y (2006) Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1-HSF2 heterocomplexes. Biochem J 395(1):223–231. doi:10.1042/BJ20051190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ostling P, Bjork JK, Roos-Mattjus P, Mezger V, Sistonen L (2007) Heat shock factor 2 (HSF2) contributes to inducible expression of hsp genes through interplay with HSF1. J Biol Chem 282(10):7077–7086. doi:10.1074/jbc.M607556200

    Article  PubMed  CAS  Google Scholar 

  38. Kroeger PE, Sarge KD, Morimoto RI (1993) Mouse heat shock transcription factors 1 and 2 prefer a trimeric binding site but interact differently with the HSP70 heat shock element. Mol Cell Biol 13(6):3370–3383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xing H, Wilkerson DC, Mayhew CN, Lubert EJ, Skaggs HS, Goodson ML, Hong Y, Park-Sarge OK, Sarge KD (2005) Mechanism of hsp70i gene bookmarking. Science 307(5708):421–423. doi:10.1126/science.1106478

    Article  CAS  PubMed  Google Scholar 

  40. Elsing AN, Aspelin C, Bjork JK, Bergman HA, Himanen SV, Kallio MJ, Roos-Mattjus P, Sistonen L (2014) Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival. J Cell Biol 206(6):735–749. doi:10.1083/jcb.201402002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tu N, Hu Y, Mivechi NF (2006) Heat shock transcription factor (Hsf)-4b recruits Brg1 during the G1 phase of the cell cycle and regulates the expression of heat shock proteins. J Cell Biochem 98(6):1528–1542. doi:10.1002/jcb.20865

    Article  CAS  PubMed  Google Scholar 

  42. Fujimoto M, Hayashida N, Katoh T, Oshima K, Shinkawa T, Prakasam R, Tan K, Inouye S, Takii R, Nakai A (2010) A novel mouse HSF3 has the potential to activate nonclassical heat-shock genes during heat shock. Mol Biol Cell 21(1):106–116. doi:10.1091/mbc.E09-07-0639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tanabe M, Nakai A, Kawazoe Y, Nagata K (1997) Different thresholds in the responses of two heat shock transcription factors, HSF1 and HSF3. J Biol Chem 272(24):15389–15395

    Article  CAS  PubMed  Google Scholar 

  44. Wang G, Ying Z, Jin X, Tu N, Zhang Y, Phillips M, Moskophidis D, Mivechi NF (2004) Essential requirement for both hsf1 and hsf2 transcriptional activity in spermatogenesis and male fertility. Genesis 38(2):66–80. doi:10.1002/gene.20005

    Article  PubMed  CAS  Google Scholar 

  45. Kawazoe Y, Tanabe M, Sasai N, Nagata K, Nakai A (1999) HSF3 is a major heat shock responsive factor duringchicken embryonic development. Eur J Biochem 265(2):688–697

    Article  CAS  PubMed  Google Scholar 

  46. Nakai A, Tanabe M, Kawazoe Y, Inazawa J, Morimoto RI, Nagata K (1997) HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Mol Cell Biol 17(1):469–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nakai A (2009) Heat shock transcription factors and sensory placode development. BMB Rep 42(10):631–635

    Article  CAS  PubMed  Google Scholar 

  48. Izu H, Inouye S, Fujimoto M, Shiraishi K, Naito K, Nakai A (2004) Heat shock transcription factor 1 is involved in quality-control mechanisms in male germ cells. Biol Reprod 70(1):18–24. doi:10.1095/biolreprod.103.020065

    Article  CAS  PubMed  Google Scholar 

  49. Fan R, Wang C, Wang Y, Ren P, Gan P, Ji H, Xia Z, Hu S, Zeng Q, Huang W, Jiang Y, Huang X (2012) Enhanced antitumoral efficacy and immune response following conditionally replicative adenovirus containing constitutive HSF1 delivery to rodent tumors. J Transl Med 10:101. doi:10.1186/1479-5876-10-101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vihervaara A, Sistonen L (2014) HSF1 at a glance. J Cell Sci 127(Pt 2):261–266. doi:10.1242/jcs.132605

    Article  CAS  PubMed  Google Scholar 

  51. Guettouche T, Boellmann F, Lane WS, Voellmy R (2005) Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem 6:4. doi:10.1186/1471-2091-6-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Holmberg CI, Hietakangas V, Mikhailov A, Rantanen JO, Kallio M, Meinander A, Hellman J, Morrice N, MacKintosh C, Morimoto RI, Eriksson JE, Sistonen L (2001) Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J 20(14):3800–3810. doi:10.1093/emboj/20.14.3800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang Y, Murshid A, Prince T, Calderwood SK (2011) Protein kinase A regulates molecular chaperone transcription and protein aggregation. PLoS One 6(12):e28950. doi:10.1371/journal.pone.0028950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Knauf U, Newton EM, Kyriakis J, Kingston RE (1996) Repression of human heat shock factor 1 activity at control temperature by phosphorylation. Genes Dev 10(21):2782–2793

    Article  CAS  PubMed  Google Scholar 

  55. Dai S, Tang Z, Cao J, Zhou W, Li H, Sampson S, Dai C (2015) Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK. EMBO J 34(3):275–293. doi:10.15252/embj.201489062

    Article  CAS  PubMed  Google Scholar 

  56. Dai C, Santagata S, Tang Z, Shi J, Cao J, Kwon H, Bronson RT, Whitesell L, Lindquist S (2012) Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J Clin Invest 122(10):3742–3754. doi:10.1172/JCI62727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tang Z, Dai S, He Y, Doty RA, Shultz LD, Sampson SB, Dai C (2015) MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell 160(4):729–744. doi:10.1016/j.cell.2015.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Santarpia L, Lippman SM, El-Naggar AK (2012) Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 16(1):103–119. doi:10.1517/14728222.2011.645805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L, Lindquist S (2012) HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150(3):549–562. doi:10.1016/j.cell.2012.06.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L (2006) Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol Cell Biol 26(3):955–964. doi:10.1128/MCB.26.3.955-964.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L (2003) Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 23(8):2953–2968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8(12):947–956. doi:10.1038/nrm2293

    Article  CAS  PubMed  Google Scholar 

  63. Brunet Simioni M, De Thonel A, Hammann A, Joly AL, Bossis G, Fourmaux E, Bouchot A, Landry J, Piechaczyk M, Garrido C (2009) Heat shock protein 27 is involved in SUMO-2/3 modification of heat shock factor 1 and thereby modulates the transcription factor activity. Oncogene 28(37):3332–3344. doi:10.1038/onc.2009.188

    Article  CAS  PubMed  Google Scholar 

  64. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323(5917):1063–1066. doi:10.1126/science.1165946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Raychaudhuri S, Loew C, Korner R, Pinkert S, Theis M, Hayer-Hartl M, Buchholz F, Hartl FU (2014) Interplay of acetyltransferase EP300 and the proteasome system in regulating heat shock transcription factor 1. Cell 156(5):975–985. doi:10.1016/j.cell.2014.01.055

    Article  CAS  PubMed  Google Scholar 

  66. Bharadwaj S, Ali A, Ovsenek N (1999) Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 in vivo. Mol Cell Biol 19(12):8033–8041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Marunouchi T, Araki M, Murata M, Takagi N, Tanonaka K (2013) Possible involvement of HSP90-HSF1 multichaperone complex in impairment of HSP72 induction in the failing heart following myocardial infarction in rats. J Pharmacol Sci 123(4):336–346

    Article  CAS  PubMed  Google Scholar 

  68. Takii R, Fujimoto M, Tan K, Takaki E, Hayashida N, Nakato R, Shirahige K, Nakai A (2015) ATF1 modulates the heat shock response by regulating the stress-inducible heat shock factor 1 transcription complex. Mol Cell Biol 35(1):11–25. doi:10.1128/MCB.00754-14

    Article  PubMed  CAS  Google Scholar 

  69. Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130(6):1005–1018. doi:10.1016/j.cell.2007.07.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li D, Yallowitz A, Ozog L, Marchenko N (2014) A gain-of-function mutant p53-HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress. Cell Death Dis 5:e1194. doi:10.1038/cddis.2014.158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jin X, Moskophidis D, Mivechi NF (2011) Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab 14(1):91–103. doi:10.1016/j.cmet.2011.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jiang S, Tu K, Fu Q, Schmitt DC, Zhou L, Lu N, Zhao Y (2015) Multifaceted roles of HSF1 in cancer. Tumour Biol 36(7):4923–4931. doi:10.1007/s13277-015-3674-x

    Article  CAS  PubMed  Google Scholar 

  73. Su KH, Cao J, Tang Z, Dai S, He Y, Sampson SB, Benjamin IJ, Dai C (2016) HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat Cell Biol 18(5):527–539. doi:10.1038/ncb3335

    Article  CAS  PubMed  Google Scholar 

  74. Kaniuk NA, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell JH (2007) Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 56(4):930–939. doi:10.2337/db06-1160

    Article  CAS  PubMed  Google Scholar 

  75. Dancso B, Spiro Z, Arslan MA, Nguyen MT, Papp D, Csermely P, Soti C (2010) The heat shock connection of metabolic stress and dietary restriction. Curr Pharm Biotechnol 11(2):139–145

    Article  CAS  PubMed  Google Scholar 

  76. Liu Y, Liu H, Yang J, Liu X, Lu S, Wen T, Xie L, Wang G (2008) Increased amyloid beta-peptide (1–40) level in brain of streptozotocin-induced diabetic rats. Neuroscience 153(3):796–802. doi:10.1016/j.neuroscience.2008.03.019

    Article  CAS  PubMed  Google Scholar 

  77. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7(4):321–331. doi:10.1006/nbdi.2000.0304

    Article  CAS  PubMed  Google Scholar 

  78. Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381–400. doi:10.1146/annurev-pharmtox-010611-134537

    Article  CAS  PubMed  Google Scholar 

  79. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226. doi:10.1016/j.molcel.2008.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Aryal P, Kim K, Park PH, Ham S, Cho J, Song K (2014) Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells. FEBS J 281(20):4644–4658. doi:10.1111/febs.12969

    Article  CAS  PubMed  Google Scholar 

  81. Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123(7):2764–2772. doi:10.1172/JCI67227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gibson GE, Starkov A, Blass JP, Ratan RR (1802) Beal MF (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1:122–134. doi:10.1016/j.bbadis.2009.08.010

    Google Scholar 

  83. Niforou K, Cheimonidou C, Trougakos IP (2014) Molecular chaperones and proteostasis regulation during redox imbalance. Redox Biol 2:323–332. doi:10.1016/j.redox.2014.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yoo HJ, Im CN, Youn DY, Yun HH, Lee JH (2014) Bis is induced by oxidative stress via activation of HSF1. Korean J Physiol Pharmacol 18(5):403–409. doi:10.4196/kjpp.2014.18.5.403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kavanagh K, Zhang L, Wagner JD (2009) Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys. Cell Stress Chaperones 14(3):291–299. doi:10.1007/s12192-008-0084-7

    Article  CAS  PubMed  Google Scholar 

  86. Perez FP, Moinuddin SS, ul ain Shamim Q, Joseph DJ, Morisaki J, Zhou X (2012) Longevity pathways: HSF1 and FoxO pathways, a new therapeutic target to prevent age-related diseases. Curr Aging Sci 5(2):87–95

    Article  CAS  PubMed  Google Scholar 

  87. Heydari AR, You S, Takahashi R, Gutsmann A, Sarge KD, Richardson A (1996) Effect of caloric restriction on the expression of heat shock protein 70 and the activation of heat shock transcription factor 1. Dev Genet 18(2):114–124. doi:10.1002/(SICI)1520-6408(1996)18:2<114:AID-DVG4>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  88. Hensen SM, Heldens L, van Enckevort CM, van Genesen ST, Pruijn GJ, Lubsen NH (2012) Heat shock factor 1 is inactivated by amino acid deprivation. Cell Stress Chaperones 17(6):743–755. doi:10.1007/s12192-012-0347-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rokutan K, Hirakawa T, Teshima S, Honda S, Kishi K (1996) Glutathione depletion impairs transcriptional activation of heat shock genes in primary cultures of guinea pig gastric mucosal cells. J Clin Invest 97(10):2242–2250. doi:10.1172/JCI118665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Barna J, Princz A, Kosztelnik M, Hargitai B, Takacs-Vellai K, Vellai T (2012) Heat shock factor-1 intertwines insulin/IGF-1, TGF-beta and cGMP signaling to control development and aging. BMC Dev Biol 12:32. doi:10.1186/1471-213X-12-32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300(5622):1142–1145. doi:10.1126/science.1083701

    Article  CAS  PubMed  Google Scholar 

  92. Chiang WC, Ching TT, Lee HC, Mousigian C, Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148(1–2):322–334. doi:10.1016/j.cell.2011.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Minsky N, Roeder RG (2015) Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1alpha. Proc Natl Acad Sci USA 112(42):E5669–E5678. doi:10.1073/pnas.1516219112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gueant JL, Elakoum R, Ziegler O, Coelho D, Feigerlova E, Daval JL, Gueant-Rodriguez RM (2014) Nutritional models of foetal programming and nutrigenomic and epigenomic dysregulations of fatty acid metabolism in the liver and heart. Pflugers Arch 466(5):833–850. doi:10.1007/s00424-013-1339-4

    Article  CAS  PubMed  Google Scholar 

  95. Yamagishi N, Nakayama K, Wakatsuki T, Hatayama T (2001) Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats. Life Sci 69(22):2603–2609

    Article  CAS  PubMed  Google Scholar 

  96. Atalay M, Oksala NK, Laaksonen DE, Khanna S, Nakao C, Lappalainen J, Roy S, Hanninen O, Sen CK (2004) Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol (1985) 97(2):605–611. doi:10.1152/japplphysiol.01183.2003

    Article  CAS  Google Scholar 

  97. Bruce CR, Carey AL, Hawley JA, Febbraio MA (2003) Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52(9):2338–2345

    Article  CAS  PubMed  Google Scholar 

  98. Kurucz I, Morva A, Vaag A, Eriksson KF, Huang X, Groop L, Koranyi L (2002) Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance. Diabetes 51(4):1102–1109

    Article  CAS  PubMed  Google Scholar 

  99. Rodrigues-Krause J, Krause M, O’Hagan C, De Vito G, Boreham C, Murphy C, Newsholme P, Colleran G (2012) Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter? Cell Stress Chaperones 17(3):293–302. doi:10.1007/s12192-011-0319-x

    Article  PubMed  PubMed Central  Google Scholar 

  100. Drew BG, Ribas V, Le JA, Henstridge DC, Phun J, Zhou Z, Soleymani T, Daraei P, Sitz D, Vergnes L, Wanagat J, Reue K, Febbraio MA, Hevener AL (2014) HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes 63(5):1488–1505. doi:10.2337/db13-0665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 105(5):1739–1744. doi:10.1073/pnas.0705799105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Henstridge DC, Bruce CR, Drew BG, Tory K, Kolonics A, Estevez E, Chung J, Watson N, Gardner T, Lee-Young RS, Connor T, Watt MJ, Carpenter K, Hargreaves M, McGee SL, Hevener AL, Febbraio MA (2014) Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes 63(6):1881–1894. doi:10.2337/db13-0967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rosas PC, Nagaraja GM, Kaur P, Panossian A, Wickman G, Garcia LR, Al-Khamis FA, Asea AA (2016) Hsp72 (HSPA1A) prevents human islet amyloid polypeptide aggregation and toxicity: a new approach for type 2 diabetes treatment. PLoS One 11(3):e0149409. doi:10.1371/journal.pone.0149409

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Literati-Nagy B, Kulcsar E, Literati-Nagy Z, Buday B, Peterfai E, Horvath T, Tory K, Kolonics A, Fleming A, Mandl J, Koranyi L (2009) Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial. Horm Metab Res 41(5):374–380. doi:10.1055/s-0028-1128142

    Article  CAS  PubMed  Google Scholar 

  105. Literati-Nagy B, Tory K, Peitl B, Bajza A, Koranyi L, Literati-Nagy Z, Hooper PL, Vigh L, Szilvassy Z (2014) Improvement of insulin sensitivity by a novel drug candidate, BGP-15, in different animal studies. Metab Syndr Relat Disord 12(2):125–131. doi:10.1089/met.2013.0098

    Article  CAS  PubMed  Google Scholar 

  106. Kondo T, Sasaki K, Matsuyama R, Morino-Koga S, Adachi H, Suico MA, Kawashima J, Motoshima H, Furukawa N, Kai H, Araki E (2012) Hyperthermia with mild electrical stimulation protects pancreatic beta-cells from cell stresses and apoptosis. Diabetes 61(4):838–847. doi:10.2337/db11-1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dai T, Patel-Chamberlin M, Natarajan R, Todorov I, Ma J, LaPage J, Phillips L, Nast CC, Becerra D, Chuang P, Tong L, de Belleroche J, Wells DJ, Wang Y, Adler SG (2009) Heat shock protein 27 overexpression mitigates cytokine-induced islet apoptosis and streptozotocin-induced diabetes. Endocrinology 150(7):3031–3039. doi:10.1210/en.2008-0732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Uchiyama T, Tomono S, Utsugi T, Ohyama Y, Nakamura T, Tomura H, Kawazu S, Okajima F, Kurabayashi M (2011) Constitutively active heat shock factor 1 enhances glucose-driven insulin secretion. Metabolism 60(6):789–798. doi:10.1016/j.metabol.2010.07.029

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Kline MP, Morimoto RI (1997) Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation. Mol Cell Biol 17(4):2107–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Geiger PC, Gupte AA (2011) Heat shock proteins are important mediators of skeletal muscle insulin sensitivity. Exerc Sport Sci Rev 39(1):34–42. doi:10.1097/JES.0b013e318201f236

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hooper PL (1999) Hot-tub therapy for type 2 diabetes mellitus. N Engl J Med 341(12):924–925. doi:10.1056/NEJM199909163411216

    Article  CAS  PubMed  Google Scholar 

  113. Gupte AA, Bomhoff GL, Swerdlow RH, Geiger PC (2009) Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes 58(3):567–578. doi:10.2337/db08-1070

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, Liu J, Finkel T, Mueller E (2015) Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1alpha transcriptional axis. Cell Metab 22(4):695–708. doi:10.1016/j.cmet.2015.08.005

    Article  CAS  PubMed  Google Scholar 

  115. Townley R, Shapiro L (2007) Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase. Science 315(5819):1726–1729. doi:10.1126/science.1137503

    Article  CAS  PubMed  Google Scholar 

  116. Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449(7161):496–500. doi:10.1038/nature06161

    Article  CAS  PubMed  Google Scholar 

  117. Stahmann N, Woods A, Carling D, Heller R (2006) Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol 26(16):5933–5945. doi:10.1128/MCB.00383-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Racioppi L, Means AR (2012) Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology. J Biol Chem 287(38):31658–31665. doi:10.1074/jbc.R112.356485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR, Carling D, Gamblin SJ (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472(7342):230–233. doi:10.1038/nature09932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Corton JM, Gillespie JG, Hardie DG (1994) Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol 4(4):315–324

    Article  CAS  PubMed  Google Scholar 

  121. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 10(20):1247–1255

    Article  CAS  PubMed  Google Scholar 

  122. Fujii N, Hayashi T, Hirshman MF, Smith JT, Habinowski SA, Kaijser L, Mu J, Ljungqvist O, Birnbaum MJ, Witters LA, Thorell A, Goodyear LJ (2000) Exercise induces isoform-specific increase in 5′AMP-activated protein kinase activity in human skeletal muscle. Biochem Biophys Res Commun 273(3):1150–1155. doi:10.1006/bbrc.2000.3073

    Article  CAS  PubMed  Google Scholar 

  123. Hawley SA, Gadalla AE, Olsen GS, Hardie DG (2002) The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51(8):2420–2425

    Article  CAS  PubMed  Google Scholar 

  124. Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229(2):558–565

    Article  CAS  PubMed  Google Scholar 

  125. Carlson CA, Kim KH (1973) Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem 248(1):378–380

    CAS  PubMed  Google Scholar 

  126. van Veelen W, Korsse SE, van de Laar L, Peppelenbosch MP (2011) The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 30(20):2289–2303. doi:10.1038/onc.2010.630

    Article  PubMed  CAS  Google Scholar 

  127. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13(15):1259–1268

    Article  CAS  PubMed  Google Scholar 

  128. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590

    Article  CAS  PubMed  Google Scholar 

  129. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282(41):30107–30119. doi:10.1074/jbc.M705325200

    Article  CAS  PubMed  Google Scholar 

  130. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4):376–388. doi:10.1016/j.cmet.2011.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lee CW, Wong LL, Tse EY, Liu HF, Leong VY, Lee JM, Hardie DG, Ng IO, Ching YP (2012) AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res 72(17):4394–4404. doi:10.1158/0008-5472.CAN-12-0429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124. doi:10.1016/S0092-8674(00)80611-X

    Article  CAS  PubMed  Google Scholar 

  133. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106(7):847–856. doi:10.1172/JCI10268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104(29):12017–12022. doi:10.1073/pnas.0705070104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99(25):15983–15987. doi:10.1073/pnas.252625599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122(6):253–270. doi:10.1042/CS20110386

    Article  CAS  Google Scholar 

  137. Moses AC, Young SC, Morrow LA, O’Brien M, Clemmons DR (1996) Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45(1):91–100

    Article  CAS  PubMed  Google Scholar 

  138. Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52(6):1083–1086. doi:10.1007/s00125-009-1347-2

    Article  CAS  PubMed  Google Scholar 

  139. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–865

    Article  Google Scholar 

  140. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. doi:10.1146/annurev.biochem.75.101304.123901

    Article  CAS  PubMed  Google Scholar 

  141. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983

    Article  Google Scholar 

  142. Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep 5(10):958–963. doi:10.1038/sj.embor.7400250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Parekh-Olmedo H, Wang J, Gusella JF, Kmiec EB (2004) Modified single-stranded oligonucleotides inhibit aggregate formation and toxicity induced by expanded polyglutamine. J Mol Neurosci 24(2):257–267. doi:10.1385/JMN:24:2:257

    Article  CAS  PubMed  Google Scholar 

  144. Chafekar SM, Duennwald ML (2012) Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One 7(5):e37929. doi:10.1371/journal.pone.0037929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Fujimoto M, Takaki E, Hayashi T, Kitaura Y, Tanaka Y, Inouye S, Nakai A (2005) Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J Biol Chem 280(41):34908–34916. doi:10.1074/jbc.M506288200

    Article  CAS  PubMed  Google Scholar 

  146. Neef DW, Turski ML, Thiele DJ (2010) Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 8(1):e1000291. doi:10.1371/journal.pbio.1000291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Hayashida N, Fujimoto M, Tan K, Prakasam R, Shinkawa T, Li L, Ichikawa H, Takii R, Nakai A (2010) Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT. EMBO J 29(20):3459–3469. doi:10.1038/emboj.2010.225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18(7):671–680

    Article  CAS  PubMed  Google Scholar 

  149. Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A (1989) X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112(Pt 1):209–232

    Article  PubMed  Google Scholar 

  150. Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621. doi:10.1146/annurev.neuro.29.051605.113042

    Article  CAS  PubMed  Google Scholar 

  151. Kondo N, Katsuno M, Adachi H, Minamiyama M, Doi H, Matsumoto S, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Ishigaki S, Fujioka Y, Watanabe H, Tanaka F, Nakai A, Sobue G (2013) Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration. Nat Commun 4:1405. doi:10.1038/ncomms2417

    Article  PubMed  CAS  Google Scholar 

  152. Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66(2):137–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357. doi:10.1038/nature04533

    Article  CAS  PubMed  Google Scholar 

  154. Chow VW, Mattson MP, Wong PC, Gleichmann M (2010) An overview of APP processing enzymes and products. Neuromolecular Med 12(1):1–12. doi:10.1007/s12017-009-8104-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739(2–3):198–210. doi:10.1016/j.bbadis.2004.09.008

    Article  CAS  PubMed  Google Scholar 

  156. Mandelkow EM, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2(7):a006247. doi:10.1101/cshperspect.a006247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A (2013) Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis 2(1):1–14

    PubMed  PubMed Central  Google Scholar 

  158. Greenwald J, Riek R (2010) Biology of amyloid: structure, function, and regulation. Structure 18(10):1244–1260. doi:10.1016/j.str.2010.08.009

    Article  CAS  PubMed  Google Scholar 

  159. Jiang YQ, Wang XL, Cao XH, Ye ZY, Li L, Cai WQ (2013) Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer’s disease. Brain Res 1519:105–111. doi:10.1016/j.brainres.2013.04.059

    Article  CAS  PubMed  Google Scholar 

  160. Guzhova I, Margulis B (2006) Hsp70 chaperone as a survival factor in cell pathology. Int Rev Cytol 254:101–149. doi:10.1016/S0074-7696(06)54003-3

    Article  CAS  PubMed  Google Scholar 

  161. 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(44):33182–33191. doi:10.1074/jbc.M606192200

    Article  CAS  PubMed  Google Scholar 

  162. Wacker JL, Huang SY, Steele AD, Aron R, Lotz GP, Nguyen Q, Giorgini F, Roberson ED, Lindquist S, Masliah E, Muchowski PJ (2009) Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington’s disease. J Neurosci 29(28):9104–9114. doi:10.1523/JNEUROSCI.2250-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hoshino T, Murao N, Namba T, Takehara M, Adachi H, Katsuno M, Sobue G, Matsushima T, Suzuki T, Mizushima T (2011) Suppression of Alzheimer’s disease-related phenotypes by expression of heat shock protein 70 in mice. J Neurosci 31(14):5225–5234. doi:10.1523/JNEUROSCI.5478-10.2011

    Article  CAS  PubMed  Google Scholar 

  164. 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 24(7):1700–1706. doi:10.1523/JNEUROSCI.4330-03.2004

    Article  CAS  PubMed  Google Scholar 

  165. 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(7):848–864. doi:10.1093/hmg/ddm030

    Article  CAS  PubMed  Google Scholar 

  166. Jinwal UK, Miyata Y, Koren J 3rd, Jones JR, Trotter JH, Chang L, O’Leary J, Morgan D, Lee DC, Shults CL, Rousaki A, Weeber EJ, Zuiderweg ER, Gestwicki JE, Dickey CA (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29(39):12079–12088. doi:10.1523/JNEUROSCI.3345-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Patterson KR, Ward SM, Combs B, Voss K, Kanaan NM, Morfini G, Brady ST, Gamblin TC, Binder LI (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. doi:10.1021/bi2009147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Thompson AD, Scaglione KM, Prensner J, Gillies AT, Chinnaiyan A, Paulson HL, Jinwal UK, Dickey CA, Gestwicki JE (2012) Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation. ACS Chem Biol 7(10):1677–1686. doi:10.1021/cb3002599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, Perry G, Shimohama S (2002) Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. Faseb J 16(6):601–603

    CAS  PubMed  Google Scholar 

  170. Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue G (2006) Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. J Mol Med (Berl) 84(8):635–646. doi:10.1007/s00109-006-0066-0

    Article  CAS  Google Scholar 

  171. Duan W, Jiang M, Jin J (2014) Metabolism in HD: still a relevant mechanism? Mov Disord 29(11):1366–1374. doi:10.1002/mds.25992

    Article  PubMed  PubMed Central  Google Scholar 

  172. Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17(1):45–58. doi:10.1385/JMN:17:1:45

    Article  CAS  PubMed  Google Scholar 

  173. Gadalla AE, Pearson T, Currie AJ, Dale N, Hawley SA, Sheehan M, Hirst W, Michel AD, Randall A, Hardie DG, Frenguelli BG (2004) AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus. J Neurochem 88(5):1272–1282

    Article  CAS  PubMed  Google Scholar 

  174. McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV (2005) Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem 280(21):20493–20502. doi:10.1074/jbc.M409985200

    Article  CAS  PubMed  Google Scholar 

  175. Ju TC, Chen HM, Chen YC, Chang CP, Chang C, Chern Y (2014) AMPK-alpha1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington’s disease. Biochim Biophys Acta 1842(9):1668–1680. doi:10.1016/j.bbadis.2014.06.012

    Article  CAS  PubMed  Google Scholar 

  176. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3(11):862–872. doi:10.1038/nrn960

    Article  CAS  PubMed  Google Scholar 

  177. Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem 111(6):1275–1308

    Article  CAS  PubMed  Google Scholar 

  178. Mosconi L, Mistur R, Switalski R, Brys M, Glodzik L, Rich K, Pirraglia E, Tsui W, De Santi S, de Leon MJ (2009) Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology 72(6):513–520. doi:10.1212/01.wnl.0000333247.51383.43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Galindo MF, Ikuta I, Zhu X, Casadesus G, Jordan J (2010) Mitochondrial biology in Alzheimer’s disease pathogenesis. J Neurochem 114(4):933–945. doi:10.1111/j.1471-4159.2010.06814.x

    CAS  PubMed  Google Scholar 

  180. Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J 434(3):503–512. doi:10.1042/BJ20101485

    Article  CAS  PubMed  Google Scholar 

  181. Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F (2013) The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation. Neuron 78(1):94–108. doi:10.1016/j.neuron.2013.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Nakatsu Y, Kotake Y, Hino A, Ohta S (2008) Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death. Toxicol Appl Pharmacol 230(3):358–363. doi:10.1016/j.taap.2008.03.021

    Article  CAS  PubMed  Google Scholar 

  183. Dagon Y, Avraham Y, Magen I, Gertler A, Ben-Hur T, Berry EM (2005) Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J Biol Chem 280(51):42142–42148. doi:10.1074/jbc.M507607200

    Article  CAS  PubMed  Google Scholar 

  184. Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF (2009) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA 106(10):3907–3912. doi:10.1073/pnas.0807991106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Barini E, Antico O, Zhao Y, Asta F, Tucci V, Catelani T, Marotta R, Xu H, Gasparini L (2016) Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener 11:16. doi:10.1186/s13024-016-0082-7

    Article  PubMed  PubMed Central  Google Scholar 

  186. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, Woodward M, Boundy K, Ellis KA, Bush AI, Faux NG, Martins R, Szoeke C, Rowe C, Watters DA (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36(10):2981–2987. doi:10.2337/dc13-0229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Ma T, Chen Y, Vingtdeux V, Zhao H, Viollet B, Marambaud P, Klann E (2014) Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid beta. J Neurosci 34(36):12230–12238. doi:10.1523/JNEUROSCI.1694-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009) Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380(1):98–104. doi:10.1016/j.bbrc.2009.01.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Greco SJ, Hamzelou A, Johnston JM, Smith MA, Ashford JW, Tezapsidis N (2011) Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and beta-amyloid in neurons. Biochem Biophys Res Commun 414(1):170–174. doi:10.1016/j.bbrc.2011.09.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67(6):953–966. doi:10.1016/j.neuron.2010.08.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA, Calon F (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68(1):48–58. doi:10.1097/NEN.0b013e3181922348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Marques-Aleixo I, Rocha-Rodrigues S, Santos-Alves E, Coxito PM, Passos E, Oliveira PJ, Magalhaes J, Ascensao A (2012) In vitro salicylate does not further impair aging-induced brain mitochondrial dysfunction. Toxicology 302(1):51–59. doi:10.1016/j.tox.2012.07.018

    Article  CAS  PubMed  Google Scholar 

  193. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15(5):675–690. doi:10.1016/j.cmet.2012.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Du LL, Chai DM, Zhao LN, Li XH, Zhang FC, Zhang HB, Liu LB, Wu K, Liu R, Wang JZ, Zhou XW (2015) AMPK activation ameliorates Alzheimer’s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer’s disease model in rats. J Alzheimers Dis 43(3):775–784. doi:10.3233/JAD-140564

    CAS  PubMed  Google Scholar 

  195. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B (2014) Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 41(1):61–68. doi:10.3233/JAD-131901

    CAS  PubMed  Google Scholar 

  196. Cohen P, Frame S (2001) The renaissance of GSK3. Nat Rev Mol Cell Biol 2(10):769–776. doi:10.1038/35096075

    Article  CAS  PubMed  Google Scholar 

  197. Park KJ, Gaynor RB, Kwak YT (2003) Heat shock protein 27 association with the I kappa B kinase complex regulates tumor necrosis factor alpha-induced NF-kappa B activation. J Biol Chem 278(37):35272–35278. doi:10.1074/jbc.M305095200

    Article  CAS  PubMed  Google Scholar 

  198. Ran R, Lu A, Zhang L, Tang Y, Zhu H, Xu H, Feng Y, Han C, Zhou G, Rigby AC, Sharp FR (2004) Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling. Genes Dev 18(12):1466–1481. doi:10.1101/gad.1188204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. 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(18):6826–6836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Copps KD, White MF (2012) Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55(10):2565–2582. doi:10.1007/s00125-012-2644-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Fujita N, Sato S, Ishida A, Tsuruo T (2002) Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem 277(12):10346–10353. doi:10.1074/jbc.M106736200

    Article  CAS  PubMed  Google Scholar 

  202. Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 277(42):39858–39866. doi:10.1074/jbc.M206322200

    Article  CAS  PubMed  Google Scholar 

  203. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277(2):1531–1537. doi:10.1074/jbc.M101521200

    Article  CAS  PubMed  Google Scholar 

  204. Pederson TM, Kramer DL, Rondinone CM (2001) Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50(1):24–31

    Article  CAS  PubMed  Google Scholar 

  205. Viollet B, Horman S, Leclerc J, Lantier L, Foretz M, Billaud M, Giri S, Andreelli F (2010) AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol 45(4):276–295. doi:10.3109/10409238.2010.488215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, Schumacker PT (2011) Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 31(17):3531–3545. doi:10.1128/MCB.05124-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We sincerely apologize to those authors whose work could not be cited in this review due to space limitations. C. D. was supported by The Jackson Laboratory Cancer Center Support Grant 3P30CA034196, Grants 1DP2OD007070 and R21CA184704 from the NIH, and the New Scholar Award AS-NS-0599-09 from the Ellison Medical Foundation.

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Su, KH., Dai, C. Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders. Cell. Mol. Life Sci. 73, 4231–4248 (2016). https://doi.org/10.1007/s00018-016-2291-1

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