Skip to main content
SpringerLink
Log in

HSF1, Aging, and Neurodegeneration

  • Chapter
  • First Online:
Cell Biology and Translational Medicine, Volume 18

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1409))

Abstract

Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging – dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.

Structured Abstracts

Introduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability.

Objectives: Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND).

Methods: We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases.

Results: We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging.

Conclusions: We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins – dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AD1 and AD2:

Activation domain

CAT:

Chloramphenicol acetyl-transferase

CR:

Caloric restriction

DBD:

DNA-binding domain

HR:

Heptad repeat (HRA/B and HRC aka LZ 1–3 and LZ4)

HSE:

Heat shock element

HSF1:

Heat shock factor 1

HSP:

Heat shock protein family

Hsp:

Specific heat shock protein

Hsp70:

70 kDa Heat shock protein

hsp70:

DNA/mRNA of the Hsp70 protein

HSR:

Heat shock response

IB:

Inclusion bodies

IDP and IDR:

Intrinsically disordered protein and intrinsically disordered region

LZ:

Leucine zipper

mHtt:

polyQ-expanded mutant huntingtin

ND:

Neurodegenerative disease

PDSM:

phosphorylation-dependent sumoylation motif

PONDR:

Predictor of Natural Disordered Regions

PTM:

Post-translation modification

QC:

Quality control

SIRT1:

Sirtuin 1

TAD:

Transactivation domain

TD:

Trimerization domain

References

  • Adelman R (1979) In pursuit of molecular mechanisms of aging. In: Physiology and cell biology of aging. Raven Press, New York, pp 99–107

    Google Scholar 

  • Åkerfelt 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Alberti S, Hyman AA (2016) Are aberrant phase transitions a driver of cellular aging? BioEssays 38(10):959–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anckar J, Sistonen L (2007) Heat shock factor 1 as a coordinator of stress and developmental pathways. In: Csermely P, Vigh L (eds) Molecular aspects of the stress response: chaperones, membranes and networks, vol 594. Springer, Berlin, pp 78–88

    Chapter  Google Scholar 

  • Anckar J, Sistonen L (2011) Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 80(1):1089–1115

    Article  CAS  PubMed  Google Scholar 

  • Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431(7010):805

    Article  CAS  PubMed  Google Scholar 

  • Babu MM (2016) The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease. Biochem Soc Trans 44(5):1185–1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batulan Z, Shinder GA, Minotti S, He BP, Doroudchi M, Nalbantoglu J, Strong MJ, Durham HD (2003) High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 23(13):5789–5798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blake MJ, Gershon D, Fargnoli J, Holbrook NJ (1990) Discordant expression of heat shock protein mRNAs in tissues of heat-stressed rats. J Biol Chem 265(25):15275–15279

    Article  CAS  PubMed  Google Scholar 

  • Blake MJ, Udelsman R, Feulner GJ, Norton DD, Holbrook NJ (1991) Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc Natl Acad Sci USA 88(21):9873–9877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG (2006) Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci 103(11):4246–4251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Byun K, Kim TK, Oh J, Bayarsaikhan E, Kim D, Lee MY, Pack CG, Hwang D, Lee B (2013) Heat shock instructs hESCs to exit from the self-renewal program through negative regulation of OCT4 by SAPK/JNK and HSF1 pathway. Stem Cell Res 11(3):1323–1334

    Article  CAS  PubMed  Google Scholar 

  • Chafekar SM, Duennwald ML (2012) Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One 7(5):e37929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen K, Qian WK, Li J, Jiang ZD, Cheng L, Yan B, Cao JY, Sun LK, Zhou CC, Lei M, Duan WX, Ma JG, Ma QY, Ma ZH (2017) Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1-dependent pathway. Mol Oncol 11(10):1475–1492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen JY, Parekh M, Seliman H, Bakshinskaya D, Dai W, Kwan K, Chen KY, Liu AYC (2018) Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction. J Biol Chem 293:15581–15593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi HS, Lin Z, Li BS, Liu AY (1990) Age-dependent decrease in the heat-inducible DNA sequence-specific binding activity in human diploid fibroblasts. J Biol Chem 265(29):18005–18011

    Article  CAS  PubMed  Google Scholar 

  • Cotto JJ, Kline M, Morimoto RI (1996) Activation of heat shock factor 1 DNA binding precedes stress-induced serine phosphorylation – evidence for a multistep pathway of regulation. J Biol Chem 271(7):3355–3358

    Article  CAS  PubMed  Google Scholar 

  • Deguchi Y, Negoro S, Kishimoto S (1988) Age-related changes of heat shock protein gene transcription in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 157(2):580–584

    Article  CAS  PubMed  Google Scholar 

  • Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J Mol Biol 347(4):827–839

    Article  CAS  PubMed  Google Scholar 

  • Dosztányi Z, Mészáros B, Simon I (2009) ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25(20):2745–2746

    Article  PubMed  PubMed Central  Google Scholar 

  • Driscoll DM (1971) The relationship between weather and mortality in ten major metropolitan areas in the United States, 1962–1965. Int J Biometeorol 15(1):23–39

    Article  CAS  PubMed  Google Scholar 

  • Dunker AK, Kriwacki RW (2011) The orderly chaos of proteins. Sci Am 304(4):68–73

    Article  CAS  PubMed  Google Scholar 

  • Dunker AK, Bondos SE, Huang F, Oldfield CJ (2015) Intrinsically disordered proteins and multicellular organisms. Semin Cell Dev Biol 37:44–55

    Article  CAS  PubMed  Google Scholar 

  • Faassen AE, O’Leary JJ, Rodysill KJ, Bergh N, Hallgren HM (1989) Diminished heat-shock protein synthesis following mitogen stimulation of lymphocytes from aged donors. Exp Cell Res 183(2):326–334

    Article  CAS  PubMed  Google Scholar 

  • Fawcett TW, Sylvester SL, Sarge KD, Morimoto RI, Holbrook NJ (1994) Effects of neurohormonal stress and aging on the activation of mammalian heat-shock factor-1. J Biol Chem 269(51):32272–32278

    Article  CAS  PubMed  Google Scholar 

  • Gasteiger E, Hoogland C, Gattiker A, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. In: The proteomics protocols handbook. Springer, New York, pp 571–607. https://link.springer.com/protocol/10.1385/1-59259-890-0:571

  • Gething M-J, Sambrook J (1992) Protein folding in the cell. Nature 355(6355):33

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Pastor R, Burchfiel ET, Thiele DJ (2018) Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol 19(1):4–19

    Article  CAS  PubMed  Google Scholar 

  • Grabowska W, Sikora E, Bielak-Zmijewska A (2017) Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18(4):447–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guarente L (2000) Sir2 links chromatin silencing, metabolism, and aging. Genes Dev 14(9):1021–1026

    Article  CAS  PubMed  Google Scholar 

  • 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(1):4

    Article  PubMed  PubMed Central  Google Scholar 

  • Gui X, Luo F, Li Y, Zhou H, Qin Z, Liu Z, Gu J, Xie M, Zhao K, Dai B, Shin WS, He J, He L, Jiang L, Zhao M, Sun B, Li X, Liu C, Li D (2019) Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly. Nat Commun 10(1):2006

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo YL, 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

    Article  CAS  PubMed  Google Scholar 

  • Gutsmann-Conrad A, Heydari AR, You SH, Richardson A (1998) The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp Cell Res 241(2):404–413

    Article  CAS  PubMed  Google Scholar 

  • Hahn GM, Li GC (1990) Thermotolerance, thermoresistance, and thermosensitization, vol. 19 (Ed: AG Morimoto R, Tissieres C) Cold Spring Harbor Monograph Archive, New York, pp 79–100

    Google Scholar 

  • Harrison CJ, Bohm AA, Nelson H (1994) Crystal structure of the DNA binding domain of the heat shock transcription factor. Science 263(5144):224–227

    Article  CAS  PubMed  Google Scholar 

  • Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475(7356):324–332

    Article  CAS  PubMed  Google Scholar 

  • Hendrick JP, Hartl F-U (1993) Molecular chaperone functions of heat-shock proteins. Annu Rev Biochem 62(1):349–384

    Article  CAS  PubMed  Google Scholar 

  • Hendrick JP, Hartl FU (1995) The role of molecular chaperones in protein folding. FASEB J 9(15):1559–1569

    Article  CAS  PubMed  Google Scholar 

  • Hentze N, Le Breton L, Wiesner J, Kempf G, Mayer MP (2016) Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1. elife 5:e11576

    Article  PubMed  PubMed Central  Google Scholar 

  • Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20(7):421–435

    Article  CAS  PubMed  Google Scholar 

  • Hooper L, Bunn D, Jimoh FO, Fairweather-Tait SJ (2014) Water-loss dehydration and aging. Mech Ageing Dev 136–137:50–58

    Article  PubMed  Google Scholar 

  • Jaeger AM, Makley LN, Gestwicki JE, Thiele DJ (2014) Genomic heat shock element sequences drive cooperative human heat shock factor 1 DNA binding and selectivity. J Biol Chem 289(44):30459–30469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joutsen J, Sistonen L (2019) Tailoring of proteostasis networks with heat shock factors. Cold Spring Harb Perspect Biol 11(4):a034066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kandel ER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 5(1):14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karvinen S, Silvennoinen M, Vainio P, Sistonen L, Koch LG, Britton SL, Kainulainen H (2016) Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins. Exp Gerontol 79:46–54

    Article  CAS  PubMed  Google Scholar 

  • Kim S-J, Tsukiyama T, Lewis MS, Wu C (1994) Interaction of the DNA-binding domain of Drosophila heat shock factor with its cognate DNA site: a thermodynamic analysis using analytical ultracentrifugation. Protein Sci 3(7):1040–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knowles TPJ, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15(6):384–396

    Article  CAS  PubMed  Google Scholar 

  • Kroeger PE, Morimoto RI (1994) Selection of new HSF1 and HSF2 DNA-binding sites reveals differences in trimer cooperativity. Mol Cell Biol 14(11):7592–7603

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kulkarni P, Uversky VN (2019) Intrinsically disordered proteins in chronic diseases. Multidisciplinary Digital Publishing Institute, Basel

    Book  Google Scholar 

  • Lakatta E, Schneider E, Rowe J (1990) Handbook of the biology of aging. Academic Press, San Diego

    Google Scholar 

  • Lee YK, Manalo D, Liu AY (1996) Heat shock response, heat shock transcription factor and cell aging. Biol Signals 5(3):180–191

    Article  CAS  PubMed  Google Scholar 

  • Lee YK, Liu DJ, Lu J, Chen KY, Liu AY (2008) Aberrant regulation and modification of heat shock factor 1 in senescent human diploid fibroblasts. J Cell Biochem 106(2):267–278

    Article  Google Scholar 

  • Li GC, Werb Z (1982) Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proc Natl Acad Sci 79(10):3218–3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li GC, Li L, Liu Y-k, Mak JY, Chen L, Lee W (1991) Thermal response of rat fibroblasts stably transfected with the human 70-kDa heat shock protein-encoding gene. Proc Natl Acad Sci 88(5):1681–1685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677

    Article  CAS  PubMed  Google Scholar 

  • 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 Mol Biol 6(5):464

    Article  CAS  Google Scholar 

  • Liu AY, Lin Z, Choi HS, Sorhage F, Li B (1989) Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem 264(20):12037–12045

    Article  CAS  PubMed  Google Scholar 

  • Liu AY, Choi HS, Lee YK, Chen KY (1991) Molecular events involved in transcriptional activation of heat shock genes become progressively refractory to heat stimulation during aging of human diploid fibroblasts. J Cell Physiol 149(3):560–566

    Article  CAS  PubMed  Google Scholar 

  • Liu AY, Lee YK, Manalo D, Huang LE (1996) Attenuated heat shock transcriptional response in aging: molecular mechanism and implication in the biology of aging. In: Stress-inducible cellular responses. Birkhäuser, Basel, pp 393–408

    Chapter  Google Scholar 

  • Liu DJ, Hammer D, Komlos D, Chen KY, Firestein BL, Liu AYC (2014) SIRT1 knockdown promotes neural differentiation and attenuates the heat shock response. J Cell Physiol 229(9):1224–1235

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Park JH, Liu AY, Chen KY (2000) Activation of heat shock factor 1 by hyperosmotic or hypo-osmotic stress is drastically attenuated in normal human fibroblasts during senescence. J Cell Physiol 184(2):183–190

    Article  CAS  PubMed  Google Scholar 

  • Manalo DJ, Lin Z, Liu AYC (2002) Redox-dependent regulation of the conformation and function of human heat shock factor 1. Biochemistry 41(8):2580–2588

    Article  CAS  PubMed  Google Scholar 

  • Manzerra P, Brown IR (1996) The neuronal stress response: nuclear translocation of heat shock proteins as an indicator of hyperthermic stress. Exp Cell Res 229(1):35–47

    Article  CAS  PubMed  Google Scholar 

  • Marcuccilli CJ, Mathur SK, Morimoto RI, Miller RJ (1996) Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock. J Neurosci 16(2):478–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margulis J, Finkbeiner S (2014) Proteostasis in striatal cells and selective neurodegeneration in Huntington’s disease. Front Cell Neurosci 8:218

    Article  PubMed  PubMed Central  Google Scholar 

  • Masser AE, Kang W, Roy J, Mohanakrishnan Kaimal J, Quintana-Cordero J, Friedländer MR, Andréasson C (2019) Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1. eLife 8:e47791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maurer-Stroh S, Debulpaep M, Kuemmerer N, De La Paz ML, Martins IC, Reumers J, Morris KL, Copland A, Serpell L, Serrano L (2010) Exploring the sequence determinants of amyloid structure using position-specific scoring matrices. Nat Methods 7(3):237

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–99

    Article  CAS  PubMed  Google Scholar 

  • Nakai A (2016) Molecular basis of HSF regulation. Nat Struct Mol Biol 23(2):93–95

    Article  CAS  PubMed  Google Scholar 

  • Neudegger T, Verghese J, Hayer-Hartl M, Hartl FU, Bracher A (2016) Structure of human heat-shock transcription factor 1 in complex with DNA. Nat Struct Mol Biol 23(2):140-+

    Article  CAS  PubMed  Google Scholar 

  • Nishimura RN, Dwyer BE (1996) Evidence for different mechanisms of induction of HSP70i: a comparison of cultured rat cortical neurons with astrocytes. Brain Res Mol Brain Res 36(2):227–239

    Article  CAS  PubMed  Google Scholar 

  • Obradovic Z, Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK (2003) Predicting intrinsic disorder from amino acid sequence. Proteins Struct Funct Bioinformatics 53(S6):566–572

    Article  CAS  Google Scholar 

  • Oechsli FW, Buechley RW (1970) Excess mortality associated with three Los Angeles september hot spells. Environ Res 3(4):277–284

    Article  CAS  PubMed  Google Scholar 

  • Olzscha H, Schermann SM, Woerner AC, Pinkert S, Hecht MH, Tartaglia GG, Vendruscolo M, Hayer-Hartl M, Hartl FU, Vabulas RM (2011) Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144(1):67–78

    Article  CAS  PubMed  Google Scholar 

  • Oza J, Yang J, Chen KY, Liu AY (2008) Changes in the regulation of heat shock gene expression in neuronal cell differentiation. Cell Stress Chaperones 13(1):73–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(6):661–672

    Article  CAS  PubMed  Google Scholar 

  • Park J-K, Kim S-J (2012) Equilibrium binding of wild-type and mutant drosophila heat shock factor DNA binding domain with HSE DNA studied by analytical ultracentrifugation. Bull Korean Chem Soc 33(6):1839–1844

    Article  CAS  Google Scholar 

  • Pattaramanon N, Sangha N, Gafni A (2007) The carboxy-terminal domain of heat-shock factor 1 is largely unfolded but can be induced to collapse into a compact, partially structured state. Biochemistry 46(11):3405–3415

    Article  CAS  PubMed  Google Scholar 

  • Privalov PL, Dragan AI, Crane-Robinson C, Breslauer KJ, Remeta DP, Minetti CA (2007) What drives proteins into the major or minor grooves of DNA? J Mol Biol 365(1):1–9

    Article  CAS  PubMed  Google Scholar 

  • Pujols J, Santos J, Pallares I, Ventura S (2018) The disordered C-Terminus of yeast Hsf1 contains a cryptic low-complexity amyloidogenic region. Int J Mol Sci 19(5):1384

    Article  PubMed  PubMed Central  Google Scholar 

  • Ravarani CN, Erkina TY, De Baets G, Dudman DC, Erkine AM, Babu MM (2018) High-throughput discovery of functional disordered regions: investigation of transactivation domains. Mol Syst Biol 14(5):e8190

    Article  PubMed  PubMed Central  Google Scholar 

  • Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18(12):571–573

    Article  CAS  Google Scholar 

  • Rose AS, Bradley AR, Valasatava Y, Duarte JM, Prlić A, Rose PW (2018) NGL viewer: web-based molecular graphics for large complexes. Bioinformatics 34(21):3755–3758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutherford SL, Zuker CS (1994) Protein folding and the regulation of signaling pathways. Cell 79(7):1129–1132

    Article  CAS  PubMed  Google Scholar 

  • Santra M, Dill KA, de Graff AMR (2019) Proteostasis collapse is a driver of cell aging and death. Proc Natl Acad Sci USA 116(44):22173–22178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schock N (1977) System integration. In: Handbook of the biology of aging. Van Nostrand Reinhold, New York, pp 639–665

    Google Scholar 

  • Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB and memory. Annu Rev Neurosci 21(1):127–148

    Article  CAS  PubMed  Google Scholar 

  • Stephens AD, Kaminski Schierle GS (2019) The role of water in amyloid aggregation kinetics. Curr Opin Struct Biol 58:115–123

    Article  CAS  PubMed  Google Scholar 

  • Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11(7):515–528

    Article  CAS  PubMed  Google Scholar 

  • Tonkiss J, Calderwood SK (2005) Regulation of heat shock gene transcription in neuronal cells. Int J Hyperth 21(5):433–444

    Article  CAS  Google Scholar 

  • Udelsman R, Blake MJ, Stagg CA, Li DG, Putney DJ, Holbrook NJ (1993) Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response. J Clin Invest 91(2):465–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uversky VN (2011) Intrinsically disordered proteins from A to Z. Int J Biochem Cell Biol 43(8):1090–1103

    Article  CAS  PubMed  Google Scholar 

  • Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 1834(5):932–951

    Article  CAS  PubMed  Google Scholar 

  • Uversky VN (2015) Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders. Front Aging Neurosci 7:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Uversky VN (2016) Dancing protein clouds: the strange biology and chaotic physics of intrinsically disordered proteins. J Biol Chem 291(13):6681–6688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uversky VN (2019) Supramolecular fuzziness of intracellular liquid droplets: liquid–liquid phase transitions, membrane-less organelles, and intrinsic disorder. Molecules 24(18):3265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804(6):1231–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Hagen M, Piebes DG, de Leeuw WC, Vuist IM, van Roon-Mom WM, Moerland PD, Verschure PJ (2017) The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model. BMC Genomics 18(1):373

    Article  PubMed  PubMed Central  Google Scholar 

  • Vashisht A, Morykwas M, Hegde AN, Argenta L, McGee MP (2018) Age-dependent changes in brain hydration and synaptic plasticity. Brain Res 1680:46–53

    Article  CAS  PubMed  Google Scholar 

  • Vihervaara A, Sistonen L (2014) HSF1 at a glance. J Cell Sci 127(Pt 2):261–266

    Article  CAS  PubMed  Google Scholar 

  • Vuister GW, Kim S-J, 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

    Article  CAS  PubMed  Google Scholar 

  • Vujanac M, Fenaroli A, Zimarino V (2005) Constitutive nuclear import and stress-regulated nucleocytoplasmic shuttling of mammalian heat-shock factor 1. Traffic 6(3):214–229

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Oza J, Bridges K, Chen KY, Liu AY (2008) Neural differentiation and the attenuated heat shock response. Brain Res 1203:39–50

    Article  CAS  PubMed  Google Scholar 

  • Yoshima T, Yura T, Yanagi H (1998) Heat shock factor 1 mediates hemin-induced hsp70 gene transcription in K562 erythroleukemia cells. J Biol Chem 273(39):25466–25471

    Article  CAS  PubMed  Google Scholar 

  • Yruela I, Oldfield CJ, Niklas KJ, Dunker AK (2017) Evidence for a strong correlation between transcription factor protein disorder and organismic complexity. Genome Biol Evol 9(5):1248–1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zagrovic B, Bartonek L, Polyansky AA (2018) RNA-protein interactions in an unstructured context. FEBS Lett 592(17):2901–2916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the contributions of our students, post-doctoral fellows, and research associates to the body of work presented in this review. We apologize to colleagues whose work was not included in our citation due to space limitation.

Funding

This research was supported by grants to AYL (NIH RO1 CA39667, NIEHS P30ES05022-17, NSF DCB84-17775, DCB90-19808, MCB99-86189, MCB02-40009, NJCSCR 05-3037); KJB (NIH GM23509, GM34469, and CA47995); and KYC (NIH RO1 CA49695, AG03578).

Disclosure of Interests

All authors declare no conflict of interest.

Ethical Approval for Studies Involving Humans

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

Ethical Approval for Studies Involving Animals

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

Author information

Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Rutgers The State University of New Jersey, Piscataway, NJ, USA

    Alice Y. Liu

  2. Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA

    Alice Y. Liu & Kenneth J. Breslauer

  3. Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey, Piscataway, NJ, USA

    Conceição A. Minetti, David P. Remeta, Kenneth J. Breslauer & Kuang Yu Chen

Authors
  1. Alice Y. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Conceição A. Minetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David P. Remeta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenneth J. Breslauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kuang Yu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alice Y. Liu .

Editor information

Editors and Affiliations

  1. Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Kursad Turksen

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Liu, A.Y., Minetti, C.A., Remeta, D.P., Breslauer, K.J., Chen, K.Y. (2022). HSF1, Aging, and Neurodegeneration. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 18. Advances in Experimental Medicine and Biology(), vol 1409. Springer, Cham. https://doi.org/10.1007/5584_2022_733

Download citation

Publish with us

Policies and ethics

Search

Navigation