HSPA6 (Hsp70B’) is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40–1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.
BennettDA (2018) Lack of benefit with idalopirdine for Alzheimer disease: Another therapeutic failure in a complex disease process. JAMA319, 123–125.
2.
DunkelP, ChaiCL, SperlaghB, HuleattPB, MatyusP (2012) Clinical utility of neuroprotective agents in neurodegenerative diseases: Current status of drug development for Alzheimer’s, Parkinson's and Huntington’s diseases, and amyotrophic lateral sclerosis. Expert Opin Investig Drugs21, 1267–1308.
3.
PrattWB, GestwickiJE, OsawaY, LiebermanAP (2015) Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu Rev Pharmacol Toxicol55, 353–371.
4.
CummingsJ, RitterA, ZhongK (2018) Clinical trials for disease-modifying therapies in Alzheimer’s disease: A primer, lessons learned, and a blueprint for the future. J Alzheimers Dis64, S3–S22.
5.
RichterK, HaslbeckM, BuchnerJ (2010) The heat shock response: life on the verge of death. Mol Cell40, 253–266.
6.
RadwanM, WoodRJ, SuiX, HattersDM (2017) When pro-teostasis goes bad: protein aggregation in the cell. IUBMB Life69, 49–54.
7.
AseaAA, BrownIR (2008) Heat shock proteins and the brain: implications for neurodegenerative diseases and neuroprotection, Springer Science+Business Media B.V.
8.
MuchowskiPJ, WackerJL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci6, 11–22.
9.
WesterheideSD, MorimotoRI (2005) Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem280, 33097–33100.
10.
SweeneyP, ParkH, BaumannM, DunlopJ, FrydmanJ, KopitoR, McCampbellA, LeblancG, VenkateswaranA, NurmiA, HodgsonR (2017) Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener6, 6.
11.
YerburyJJ, OoiL, DillinA, SaundersDN, HattersDM, BeartPM, CashmanNR, WilsonMR, EcroydH (2016) Walking the tightrope: proteostasis and neurodegenerative disease. J Neurochem137, 489–505.
12.
LabbadiaJ, MorimotoRI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem84, 435–464.
13.
KampingaHH, BerginkS (2016) Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol15, 748–759.
14.
PaulS, MahantaS (2014) Association of heat-shock proteins in various neurodegenerative disorders: is it a master key to open the therapeutic door. Mol Cell Biochem386, 45–61.
DeaneCAS, BrownIR (2017) Knockdown of heat shock proteins HSPA6 (Hsp70B’) and HSPA1A (Hsp70-1) sensitizes differentiated human neuronal cells to cellular stress. Neurochem Res43, 340–350.
17.
ParsianAJ, SherenJE, TaoTY, GoswamiPC, MalyapaR, Van RheedenR, WatsonMS, HuntCR (2000) The human Hsp70B gene at the HSPA7 locus of chromosome 1 is transcribed but non-functional. Biochim Biophys Acta1494, 201–205.
18.
DeaneCA, BrownIR (2016) Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol. Cell Stress Chaperones21, 837–848.
19.
ChowAM, BrownIR (2007) Induction of heat shock proteins in differentiated human and rodent neurons by celastrol. Cell Stress Chaperones12, 237–244.
20.
SantpereG, Garcia-EsparciaP, Andres-BenitoP, Lorente-GaldosB, NavarroA, FerrerI (2018) Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies. Brain Pathol28, 315–333.
21.
Henderson-SmithA, CorneveauxJJ, De BothM, CuyuganL, LiangWS, HuentelmanM, AdlerC, Driver-DunckleyE, BeachTG, DunckleyTL (2016) Next-generation profiling to identify the molecular etiology of Parkinson dementia. Neurol Genet2, e75.
22.
AnneseA, ManzariC, LionettiC, PicardiE, HornerDS, ChiaraM, CaratozzoloMF, TulloA, FossoB, PesoleG, D'ErchiaAM (2018) Whole transcriptome profiling of Late-Onset Alzheimer’s Disease patients provides insights into the molecular changes involved in the disease. Sci Rep8, 4282.
23.
KoreckaJA, van KesterenRE, BlaasE, SpitzerSO, KamstraJH, SmitAB, SwaabDF, VerhaagenJ, BossersK (2013) Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One8, e63862.
24.
ChowAM, MokP, XiaoD, KhaloueiS, BrownIR (2010) Heteromeric complexes of heat shock protein 70 (HSP70) family members, including Hsp70B', in differentiated human neuronal cells. Cell Stress Chaperones15, 545–553.
25.
BangY, KangBY, ChoiHJ (2014) Preconditioning stimulus of proteasome inhibitor enhances aggresome formation and autophagy in differentiated SH-SY5Y cells. Neurosci Lett566, 263–268.
26.
BangY, KimKS, SeolW, ChoiHJ (2016) LRRK2 interferes with aggresome formation for autophagic clearance. Mol Cell Neurosci75, 71–80.
27.
ShenD, ColemanJ, ChanE, NicholsonTP, DaiL, SheppardPW, PattonWF (2011) Novel cell- and tissue-based assays for detecting misfolded and aggregated protein accumulation within aggresomes and inclusion bodies. Cell Biochem Biophys60, 173–185.
28.
DeaneCAS, BrownIR (2017) Differential targeting of Hsp70 heat shock proteins HSPA6 and HSPA1A with components of a protein disaggregation/refolding machine in differentiated human neuronal cells following thermal stress. Front Neurosci11, 227.
29.
BecirovicL, BrownIR (2017) Targeting of heat shock protein HSPA6 (HSP70B') to the periphery of nuclear speckles is disrupted by a transcription inhibitor following thermal stress in human neuronal cells. Neurochem Res42, 406–414.
30.
KhaloueiS, ChowAM, BrownIR (2014) Localization of heat shock protein HSPA6 (HSP70B') to sites of transcription in cultured differentiated human neuronal cells following thermal stress. J Neurochem131, 743–754.
31.
ShorbagiS, BrownIR (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 Chaperones21, 993–1003.
32.
SharmaA, TakataH, ShibaharaK, BubulyaA, BubulyaPA (2010) SON is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell21, 650–663.
33.
SytnikovaYA, KubarenkoAV, SchaferA, WeberAN, NiehrsC (2011) Gadd45a is an RNA binding protein and is localized in nuclear speckles. PLoS One6, e14500.
34.
BrownJM, GreenJ, das NevesRP, WallaceHA, SmithAJ, HughesJ, GrayN, TaylorS, WoodWG, HiggsDR, IborraFJ, BuckleVJ (2008) Association between active genes occurs at nuclear speckles and is modulated by chromatin environment. J Cell Biol182, 1083–1097.
35.
LamondAI, SpectorDL (2003) Nuclear speckles: A model for nuclear organelles. Nat Rev Mol Cell Biol4, 605–612.
Hernandez-VerdunD, RousselP, ThiryM, SirriV, LafontaineDL (2010) The nucleolus: Structure/function relationship in RNA metabolism. Wiley Interdiscip Rev RNA1, 415–431.
38.
RaskaI, ShawPJ, CmarkoD (2006) Structure and function of the nucleolus in the spotlight. Curr Opin Cell Biol18, 325–334.
39.
ThiryM, LafontaineDL (2005) Birth of a nucleolus: The evolution of nucleolar compartments. Trends Cell Biol15, 194–199.
40.
McGonigleP, RuggeriB (2014) Animal models of human disease: Challenges in enabling translation. Biochem Pharmacol87, 162–171.
41.
SasakiE (2015) Prospects for genetically modified nonhuman primate models, including the common marmoset. NeurosciRes93, 110–115.
42.
RossRA, SpenglerBA, BiedlerJL (1983) Coordinate morphological and biochemical interconversion of human neuroblastoma cells. J Natl Cancer Inst71, 741–747.
43.
KovalevichJ, LangfordD (2013) Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol1078, 9–21.
44.
MattooRU, GoloubinoffP (2014) Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. Cell Mol Life Sci71, 3311–3325.
45.
NillegodaNB, BukauB (2015) Metazoan Hsp70-based protein disaggregases: Emergence and mechanisms. Front Mol Biosci2, 57.
46.
RampeltH, Kirstein-MilesJ, NillegodaNB, ChiK, ScholzSR, MorimotoRI, BukauB (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBOJ31,4221–4235.
DuennwaldML, EcheverriaA, ShorterJ (2012) Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biol10, e1001346.
50.
EhrnspergerM, GraberS, GaestelM, BuchnerJ (1997) Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. EMBOJ16, 221–229.
51.
ChenS, BrownIR (2007) Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases. Cell Stress Chaperones12, 51–58.
52.
ManzerraP, RushSJ, BrownIR (1997) Tissue-specific differences in heat shock protein hsc70 and hsp70 in the control and hyperthermic rabbit. J Cell Physiol170, 130–137.
53.
KirsteinJ, ArnsburgK, SciorA, SzlachcicA, GuilbrideDL, MorimotoRI, BukauB, NillegodaNB (2017) In vivo properties of the disaggregase function of J-proteins and Hsc70 in Caenorhabditis elegans stress and aging. Aging Cell16, 1414–1424.
54.
DeaneCA, BrownIR (2017) Components of a mammalian protein disaggregation/refolding machine are targeted to nuclear speckles following thermal stress in differentiated human neuronal cells. Cell Stress Chaperones22, 191–200.
55.
FinkaA, GoloubinoffP (2013) Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones18, 591–605.
56.
FinkaA, SoodV, QuadroniM, Rios PdeL, GoloubinoffP (2015) Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of house-eeping proteins to massively accumulate few Hsps. Cell ress Chaperones20, 605–620.
