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Engineering Chaperones for Alzheimer’s Disease: Insights from Drosophila Models

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Heat Shock Proteins in Neuroscience

Part of the book series: Heat Shock Proteins ((HESP,volume 20))

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Abstract

Heat shock proteins (Hsp) are involved in proper folding of nascent proteins along with re-folding of misfolded proteins and degradation of proteinaceous aggregates. Among these, the heat shock protein 70 (Hsp70) plays important neuroprotective roles in several CNS proteinopathies including Alzheimer’s disease (AD). Interestingly, Hsp70 can bind and refold a wide repertoire of substrates in vitro. However, in the context of living organisms, the ability of this chaperone to interact with misfolded substrates depends on their subcellular localization. To bypass this limitation, and to specifically target extracellular deposition of amyloid-β42 (Aβ42) in vivo, we recently created a secreted version of Hsp70 (secHsp70) upon genetic engineering with signal peptides. Thus, in this chapter, we will review the protective effects of secHsp70 in a Drosophila model of AD expressing extracellular Aβ42. Special emphasis will be placed in the robust protection of secHsp70 against Aβ42 aggregation, neurodegeneration and memory impairments relative to the wild-type version of the chaperone. The successful targeting of secHsp70 against Aβ42-related phenotypes in the fly CNS suggests that this approach could be expanded to other extracellular amyloids. Therefore, we anticipate that additional chaperones engineered with different subcellular localization signals will provide new therapeutic insights for AD and related disorders.

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Abbreviations

Aβ42:

Amyloid-β42

AD:

Alzheimer’s disease

ADP:

Adenosine diphosphate

ALS:

Amyotrophic lateral sclerosis

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic

APP:

Amyloid precursor protein

APPL:

APP-like

ATP:

Adenosine triphosphate

CaMKK2:

Calmoduline kinase kinase 2

CNS:

Central nervous system

cytHsp70:

Cytosolic Hsp70

GSK3:

Glycogen synthase kinase 3

HSF1:

Heat shock factor 1

Hsp:

Heat shock protein

Hsp70:

70-kDa heat shock protein

Htt:

Huntingtin

JunK:

c-jun N-terminal kinase

MB:

Mushroom body

MD:

Middle domain

nAchR:

Nicotinic acetyl choline receptor

NBD:

Nucleotide binding domain

NFT:

Neurofibrillary tangles

NMDA:

N-methyl-D-aspartate

SBD:

Substrate binding domain

secHsp70:

Secreted Hsp70

STI1:

Stress-inducible phophoprotein 1

References

  • Anon (2018) 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14:367–429

    Article  Google Scholar 

  • Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8:1185–1186

    Article  CAS  PubMed  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  CAS  PubMed  Google Scholar 

  • Bourdet I, Lampin-Saint-Amaux A, Preat T, Goguel V (2015) Amyloid-β peptide exacerbates the memory deficit caused by amyloid precursor protein loss-of-function in Drosophila. PLoS One 10:e0135741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P (2011) The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum Mol Genet 20:2144–2160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H-JJ, Mitchell JC, Novoselov S et al (2016) The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain 139:1417–1432

    Article  PubMed  PubMed Central  Google Scholar 

  • Ciechanover A, Kwon YT (2017) Protein quality control by molecular chaperones in neurodegeneration. Front Neurosci 11:185

    Article  PubMed  PubMed Central  Google Scholar 

  • Danzer KM, Ruf WP, Putcha P et al (2011) Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J 25:326–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dedmon MM, Christodoulou J, Wilson MR, Dobson CM (2005) Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 280:14733–14740

    Article  CAS  PubMed  Google Scholar 

  • De Mena L, Chhangani D, Fernandez-Funez P, Rincon-Limas DE (2017) secHsp70 as a tool to approach amyloid-β42 and other extracellular amyloids. Fly (Austin) 11:179–184

    Article  Google Scholar 

  • Evans CG, Wisén S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 281:33182–33191

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Funez P, Casas-Tinto S, Zhang Y et al (2009) In vivo generation of neurotoxic prion protein: role for hsp70 in accumulation of misfolded isoforms. PLoS Genet 5:e1000507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fernandez-Funez P, de Mena L, Rincon-Limas DE (2015a) Modeling the complex pathology of Alzheimer’s disease in Drosophila. Exp Neurol 274:58–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fernandez-Funez P, Zhang Y, Sanchez-Garcia J et al (2015b) Anti-Aβ single-chain variable fragment antibodies exert synergistic neuroprotective activities in Drosophila models of Alzheimer’s disease. Hum Mol Genet 24:6093–6105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fernandez-Funez P, Sanchez-Garcia J, de Mena L et al (2016) Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila. Proc Natl Acad Sci U S A 113:E5212–E5221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freibaum BD, Chitta RK, High AA, Taylor JP (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9:1104–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goguel V, Belair A-LL, Ayaz D et al (2011) Drosophila amyloid precursor protein-like is required for long-term memory. J Neurosci 31:1032–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo JL, Lee VM (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  • Iijima K, Liu H-PP, Chiang A-SS, Hearn SA, Konsolaki M, Zhong Y (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci U S A 101:6623–6628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iijima K, Chiang H-CC, Hearn SA et al (2008) Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. PLoS One 3:e1703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jana NR, Tanaka M, G h W, Nukina N (2000) Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum Mol Genet 9:2009–2018

    Article  CAS  PubMed  Google Scholar 

  • Jiang J, Prasad K, Lafer EM, Sousa R (2005) Structural basis of interdomain communication in the Hsc70 chaperone. Mol Cell 20:513–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karagöz GE, Duarte AM, Akoury E et al (2014) Hsp90-tau complex reveals molecular basis for specificity in chaperone action. Cell 156:963–974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–1840

    Article  CAS  PubMed  Google Scholar 

  • Keene AC, Waddell S (2007) Drosophila olfactory memory: single genes to complex neural circuits. Nat Rev Neurosci 8:341–354

    Article  CAS  PubMed  Google Scholar 

  • Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502

    Article  CAS  PubMed  Google Scholar 

  • Kosmidis S, Grammenoudi S, Papanikolopoulou K, Skoulakis EM (2010) Differential effects of Tau on the integrity and function of neurons essential for learning in Drosophila. J Neurosci 30:464–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lackie RE, Maciejewski A, Ostapchenko VG et al (2017) The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front Neurosci 11:254

    Article  PubMed  PubMed Central  Google Scholar 

  • Lindersson E, Beedholm R, Højrup P et al (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279:12924–12934

    Article  CAS  PubMed  Google Scholar 

  • Luk KC, Mills IP, Trojanowski JQ, Lee VM (2008) Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly. Biochemistry 47:12614–12625

    Article  CAS  PubMed  Google Scholar 

  • Mannini B, Cascella R, Zampagni M et al (2012) Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers. Proc Natl Acad Sci U S A 109:12479–12484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martín-Peña A, Ferrús A (2019) A novel anesthesia-resistant memory gene, central complex broad, is involved in axonal transport. J Neurosci

    Google Scholar 

  • Martin-Peña A, Rincon-Limas DE, Fernandez-Funez P (2017) Anti-Aβ single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer’s disease. Sci Rep 7:11268

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martín-Peña A, Rincón-Limas DE, Fernandez-Fúnez P (2018) Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease. Sci Rep 8:9915

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McLean PJ, Klucken J, Shin Y, Hyman BT (2004) Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321:665–669

    Article  CAS  PubMed  Google Scholar 

  • Mershin A, Pavlopoulos E, Fitch O, Braden BC, Nanopoulos DV, Skoulakis EM (2004) Learning and memory deficits upon TAU accumulation in Drosophila mushroom body neurons. Learn Mem 11:277–287

    Article  PubMed  PubMed Central  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 12:3788–3796

    Article  CAS  PubMed  Google Scholar 

  • Opazo JC, Hoffmann FG, Storz JF (2008) Genomic evidence for independent origins of beta-like globin genes in monotremes and therian mammals. Proc Natl Acad Sci U S A 105:1590–1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Overk CR, Masliah E (2014) Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol 88:508–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM (2010) Phosphorylation differentiates tau-dependent neuronal toxicity and dysfunction. Biochem Soc Trans 38:981–987

    Article  CAS  PubMed  Google Scholar 

  • Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Schlecht R, Erbse AH, Bukau B, Mayer MP (2011) Mechanics of Hsp70 chaperones enables differential interaction with client proteins. Nat Struct Mol Biol 18:345–351

    Article  CAS  PubMed  Google Scholar 

  • Udan-Johns M, Bengoechea R, Bell S et al (2014) Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet 23:157–170

    Article  CAS  PubMed  Google Scholar 

  • Wacker JL, Huang S-YY, Steele AD et al (2009) Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington’s disease. J Neurosci 29:9104–9114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warrick JM, Paulson HL, Gray-Board GL et al (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93:939–949

    Article  CAS  PubMed  Google Scholar 

  • Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23:425–428

    Article  CAS  PubMed  Google Scholar 

  • Wyatt AR, Yerbury JJ, Ecroyd H, Wilson MR (2013) Extracellular chaperones and proteostasis. Annu Rev Biochem 82:295–322

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y-JJ, Gendron TF, Xu Y-FF, Ko L-WW, Yen S-HH, Petrucelli L (2010) Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments. Mol Neurodegener 5:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou Y, Gu G, Goodlett DR et al (2004) Analysis of alpha-synuclein-associated proteins by quantitative proteomics. J Biol Chem 279:39155–39164

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institute of Health grant R21NS081356 to D.E.R.-L.

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Authors and Affiliations

  1. Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Alfonso Martín-Peña & Diego E. Rincon-Limas

  2. Center for Smell and Taste, University of Florida, Gainesville, FL, USA

    Alfonso Martín-Peña

  3. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and Genetics Institute, University of Florida, Gainesville, FL, USA

    Diego E. Rincon-Limas

Authors
  1. Alfonso Martín-Peña
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  2. Diego E. Rincon-Limas
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Corresponding authors

Correspondence to Alfonso Martín-Peña or Diego E. Rincon-Limas .

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Editors and Affiliations

  1. Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Martín-Peña, A., Rincon-Limas, D.E. (2019). Engineering Chaperones for Alzheimer’s Disease: Insights from Drosophila Models. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Neuroscience. Heat Shock Proteins, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-24285-5_15

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