Abstract
Heat shock proteins (Hsps) are a set of highly conserved proteins involved in cellular repair and protective mechanisms. They counter protein misfolding and aggregation that are characteristic features of neurodegenerative diseases. Hsps act co-operatively in disaggregation/refolding machines that assemble at sites of protein misfolding and aggregation. Members of the DNAJ (Hsp40) family act as “holdases” that detect and bind misfolded proteins, while members of the HSPA (Hsp70) family act as “foldases” that refold proteins to biologically active states. HSPH1 (Hsp105α) is an important additional member of the mammalian disaggregation/refolding machine that acts as a disaggregase to promote the dissociation of aggregated proteins. Components of a disaggregation/refolding machine were targeted to nuclear speckles after thermal stress in differentiated human neuronal SH-SY5Y cells, namely: HSPA1A (Hsp70-1), DNAJB1 (Hsp40-1), DNAJA1 (Hsp40-4), and HSPH1 (Hsp105α). Nuclear speckles are rich in RNA splicing factors, and heat shock disrupts RNA splicing which recovers after stressful stimuli. Interestingly, constitutively expressed HSPA8 (Hsc70) was also targeted to nuclear speckles after heat shock with elements of a disaggregation/refolding machine. Hence, neurons have the potential to rapidly assemble a disaggregation/refolding machine after cellular stress using constitutively expressed Hsc70 without the time lag needed for synthesis of stress-inducible Hsp70. Constitutive Hsc70 is abundant in neurons in the mammalian brain and has been proposed to play a role in pre-protecting neurons from cellular stress.
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References
Abbott A (2002) Neurologists strike gold in drug screen effort. Nature 417:109. doi:10.1038/417109a
Asea AA, Brown IR (eds) (2008) Heat shock proteins and the brain: implications for neurodegenerative diseases and neuroprotection. Springer Science + Business Media B.V.
Biamonti G (2004) Nuclear stress bodies: a heterochromatin affair? Nat Rev Mol Cell Biol 5:493–498. doi:10.1038/nrm1405
Biamonti G, Caceres JF (2009) Cellular stress and RNA splicing. Trends Biochem Sci 34:146–153
Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ (2013) Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol 125:777–794. doi:10.1007/s00401-013-1125-6
Bosl B, Grimminger V, Walter S (2006) The molecular chaperone Hsp104—a molecular machine for protein disaggregation. J Struct Biol 156:139–148. doi:10.1016/j.jsb.2006.02.004
Bracher A, Verghese J (2015a) GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones. Subcell Biochem 78:1–33. doi:10.1007/978-3-319-11731-7_1
Bracher A, Verghese J (2015b) The nucleotide exchange factors of Hsp70 molecular chaperones. Front Mol Biosci 2:10. doi:10.3389/fmolb.2015.00010
Brehme M, Voisine C (2016) Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity. Dis Model Mech 9:823–838
Chen S, Brown IR (2007) Translocation of constitutively expressed heat shock protein Hsc70 to synapse-enriched areas of the cerebral cortex after hyperthermic stress. J Neurosci Res 85:402–409. doi:10.1002/jnr.21124
Chow AM, Mok P, Xiao D, Khalouei S, Brown IR (2010) Heteromeric complexes of heat shock protein 70 (HSP70) family members, including Hsp70B, in differentiated human neuronal cells. Cell Stress Chaperones 15:545–553. doi:10.1007/s12192-009-0167-0
Cleren C, Calingasan NY, Chen J, Beal MF (2005) Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. J Neurochem 94:995–1004. doi:10.1111/j.1471-4159.2005.03253.x
Clerico EM, Tilitsky JM, Meng W, Gierasch LM (2015) How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J Mol Biol 427:1575–1588. doi:10.1016/j.jmb.2015.02.004
Corell RA, Gross RH (1992) Splicing thermotolerance maintains pre-mRNA transcripts in the splicing pathway during severe heat shock. Exp Cell Res 202:233–242
Deane CA, Brown IR (2016) Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol. Cell Stress Chaperones. doi:10.1007/s12192-016-0708-2
Denegri M, Chiodi I, Corioni M, Cobianchi F, Riva S, Biamonti G (2001) Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors. Mol Biol Cell 12:3502–3514
Drujan D, De Maio A (1999) Expression of HSP70 is impaired at the transcriptional level in stressed murine neuroblastoma cells. Shock 12:443–448
Duennwald ML, Echeverria A, Shorter J (2012) Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biol 10:e1001346
Duncan EJ, Cheetham ME, Chapple JP, van der Spuy J (2015) The role of HSP70 and its co-chaperones in protein misfolding, aggregation and disease. Subcell Biochem 78:243–273. doi:10.1007/978-3-319-11731-7_12
Ehrnsperger M, Graber S, Gaestel M, Buchner J (1997) Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. EMBO J 16:221–229. doi:10.1093/emboj/16.2.221
Gao X et al (2015) Human Hsp70 disaggregase reverses Parkinson's-linked alpha-synuclein amyloid fibrils. Mol Cell 59:781–793. doi:10.1016/j.molcel.2015.07.012
Genc B, Ozdinler PH (2013) Moving forward in clinical trials for ALS: motor neurons lead the way please Drug. Discov Today
Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82
Hageman J, van Waarde MA, Zylicz A, Walerych D, Kampinga HH (2011) The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities. Biochem J 435:127–142. doi:10.1042/BJ20101247
Heemskerk J, Tobin AJ, Bain LJ (2002) Teaching old drugs new tricks. Meeting of the neurodegeneration drug screening consortium, 7–8 April 2002, Washington, DC, USA Trends Neurosci 25:494–496
Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L (2008) Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS. J Neurochem 107:339–350
Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592
Kampinga HH et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111. doi:10.1007/s12192-008-0068-7
Khalouei S, Chow AM, Brown IR (2014a) Localization of heat shock protein HSPA6 (HSP70B') to sites of transcription in cultured differentiated human neuronal cells following thermal stress. J Neurochem 131:743–754. doi:10.1111/jnc.12970
Khalouei S, Chow AM, Brown IR (2014b) Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (HSP70-1) proteins to centrioles in human neuronal cells. Cell Stress Chaperones 19:321–327. doi:10.1007/s12192-013-0459-2
Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY, Beal MF (2005) Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis 2:246–254. doi:10.1159/000090364
Lamond AI, Spector DL (2003) Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4:605–612. doi:10.1038/nrm1172
Lee GJ, Roseman AM, Saibil HR, Vierling E (1997) A small heat shock protein stably binds heat-denatured model substrates and can maintain a substrate in a folding-competent state. EMBO J 16:659–671. doi:10.1093/emboj/16.3.659
Lee SJ (2003) Alpha-synuclein aggregation: a link between mitochondrial defects and Parkinson's disease? Antioxid Redox Signal 5:337–348. doi:10.1089/152308603322110904
Malik B, Nirmalananthan N, Gray AL, La Spada AR, Hanna MG, Greensmith L (2013) Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy. Brain 136:926–943
Manzerra P, Rush SJ, Brown IR (1997) Tissue-specific differences in heat shock protein hsc70 and hsp70 in the control and hyperthermic rabbit. J Cell Physiol 170:130–137
Marin-Vinader L, Shin C, Onnekink C, Manley JL, Lubsen NH (2006) Hsp27 enhances recovery of splicing as well as rephosphorylation of SRp38 after heat shock. Mol Biol Cell 17:886–894. doi:10.1091/mbc.E05-07-0596
Mattoo RU, Goloubinoff P (2014) Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. Cell Mol Life Sci 71:3311–3325. doi:10.1007/s00018-014-1627-y
Mogk A, Deuerling E, Vorderwulbecke S, Vierling E, Bukau B (2003) Small heat shock proteins, ClpB and the DnaK system form a functional triade in reversing protein aggregation. Mol Microbiol 50:585–595
Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22
Nagai Y, Popiel HA (2008) Conformational changes and aggregation of expanded polyglutamine proteins as therapeutic targets of the polyglutamine diseases: exposed beta-sheet hypothesis. Curr Pharm Des 14:3267–3279
Nillegoda NB, Bukau B (2015) Metazoan Hsp70-based protein disaggregases: emergence and mechanisms. Front Mol Biosci 2:57. doi:10.3389/fmolb.2015.00057
Nillegoda NB et al (2015) Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature 524:247–251. doi:10.1038/nature14884
Ogawa M, Furukawa Y (2014) A seeded propagation of Cu, Zn-superoxide dismutase aggregates in amyotrophic lateral sclerosis. Front Cell Neurosci 8:83. doi:10.3389/fncel.2014.00083
Parfitt DA et al (2014) The heat-shock response co-inducer arimoclomol protects against retinal degeneration in rhodopsin retinitis pigmentosa. Cell Death Dis 5:e1236
Paris D et al (2010) Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 7:17. doi:10.1186/1742-2094-7-17
Paul S, Mahanta S (2014) Association of heat-shock proteins in various neurodegenerative disorders: is it a master key to open the therapeutic door? Mol Cell Biochem 386:45–61. doi:10.1007/s11010-013-1844-y
Pei JJ, Sjogren M, Winblad B (2008) Neurofibrillary degeneration in Alzheimer’s disease: from molecular mechanisms to identification of drug targets. Curr Opin Psychiatry 21:555–561. doi:10.1097/YCO.0b013e328314b78b
Rampelt H, Kirstein-Miles J, Nillegoda NB, Chi K, Scholz SR, Morimoto RI, Bukau B (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J 31:4221–4235
Salminen A, Lehtonen M, Paimela T, Kaarniranta K (2010) Celastrol: molecular targets of thunder god vine. Biochem Biophys Res Commun 394:439–442. doi:10.1016/j.bbrc.2010.03.050
Schuermann JP et al (2008) Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell 31:232–243. doi:10.1016/j.molcel.2008.05.006
Seeman P, Seeman N (2011) Alzheimer’s disease: beta-amyloid plaque formation in human brain. Synapse 65:1289–1297. doi:10.1002/syn.20957
Sharma A, Takata H, Shibahara K, Bubulya A, Bubulya PA (2010) Son is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell 21:650–663
Shorbagi S, Brown IR (2016) Dynamics of the association of heat shock protein HSPA6 (Hsp70B') and HSPA1A (Hsp70-1) with stress-sensitive cytoplasmic and nuclear structures in differentiated human neuronal cells. Cell Stress Chaperones. doi:10.1007/s12192-016-0724-2
Smith HL, Li W, Cheetham ME (2015) Molecular chaperones and neuronal proteostasis Semin. Cell Dev Biol 40:142–152
Spector DL, Lamond AI (2011) Nuclear speckles Cold Spring. Harb Perspect Biol 3 doi:10.1101/cshperspect.a000646
Sytnikova YA, Kubarenko AV, Schafer A, Weber AN, Niehrs C (2011) Gadd45a is an RNA binding protein and is localized in nuclear speckles. PLoS One 6:e14500. doi:10.1371/journal.pone.0014500
Tyedmers J, Mogk A, Bukau B (2010) Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol 11:777–788
Weibezahn J, Schlieker C, Tessarz P, Mogk A, Bukau B (2005) Novel insights into the mechanism of chaperone-assisted protein disaggregation. Biol Chem 386:739–744. doi:10.1515/BC.2005.086
Westerheide SD et al (2004) Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279:56053–56060. doi:10.1074/jbc.M409267200
Yost HJ, Lindquist S (1986) RNA splicing is interrupted by heat shock and is rescued by heat shock protein synthesis. Cell 45:185–193
Yost HJ, Lindquist S (1991) Heat shock proteins affect RNA processing during the heat shock response of Saccharomyces cerevisiae. Mol Cell Biol 11:1062–1068
Zhang YQ, Sarge KD (2007) Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response. J Mol Med (Berl) 85:1421–1428. doi:10.1007/s00109-007-0251-9
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Supported by grants from NSERC to I.R.B.
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Deane, C.A.S., Brown, I.R. Components of a mammalian protein disaggregation/refolding machine are targeted to nuclear speckles following thermal stress in differentiated human neuronal cells. Cell Stress and Chaperones 22, 191–200 (2017). https://doi.org/10.1007/s12192-016-0753-x
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DOI: https://doi.org/10.1007/s12192-016-0753-x