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Protein Aggregation in the Pathogenesis of Ischemic Stroke

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Abstract

Despite the distinction between ischemic stroke and neurodegenerative disorders, they share numerous pathophysiologies particularly those mediated by inflammation and oxidative stress. Although protein aggregation is considered to be a hallmark of neurodegenerative diseases, the formation of protein aggregates can be also induced within a short time after cerebral ischemia, aggravating cerebral ischemic injury. Protein aggregation uncovers a previously unappreciated molecular overlap between neurodegenerative diseases and ischemic stroke. Unfortunately, compared with neurodegenerative disease, mechanism of protein aggregation after cerebral ischemia and how this can be averted remain unclear. This review highlights current understanding on protein aggregation and its intrinsic role in ischemic stroke.

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References

  • Akutsu M, Dikic I, Bremm A (2016) Ubiquitin chain diversity at a glance. J Cell Sci 129(5):875–880

    CAS  PubMed  Google Scholar 

  • Alberts MJ (2017) Stroke treatment with intravenous tissue-type plasminogen activator: more proof that time is brain. Circulation 135(2):140–142

    PubMed  Google Scholar 

  • Alonso A, Zaidi T, Novak M et al (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA 98(12):6923–6928

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ambadipudi S, Biernat J, Riedel D et al (2017) Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun 8(1):275

    PubMed  PubMed Central  Google Scholar 

  • An C, Shi Y, Li P et al (2014) Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol 115:6–24

    CAS  PubMed  Google Scholar 

  • Armakola M, Higgins MJ, Figley MD et al (2012) Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet 44(12):1302–1309

    CAS  PubMed  PubMed Central  Google Scholar 

  • Atkin JD, Farg MA, Turner BJ et al (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281(40):30152–30165

    CAS  PubMed  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ et al (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556):865–868

    CAS  PubMed  Google Scholar 

  • Ayala YM, De Conti L, Avendano-Vazquez SE et al (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J 30(2):277–288

    CAS  PubMed  Google Scholar 

  • Bai Y, Zhang Y, Han B et al (2018) Circular RNA DLGAP4 ameliorates ischemic stroke outcomes by targeting miR-143 to regulate endothelial-mesenchymal transition associated with blood-brain barrier integrity. J Neurosci 38(1):32–50

    CAS  PubMed  PubMed Central  Google Scholar 

  • Banani SF, Lee HO, Hyman AA et al (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18(5):285–298

    CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee K, Sinha M, Pham Cle L et al (2010) Alpha-synuclein induced membrane depolarization and loss of phosphorylation capacity of isolated rat brain mitochondria: implications in Parkinson's disease. FEBS Lett 584(8):1571–1576

    CAS  PubMed  Google Scholar 

  • Bendor JT, Logan TP, Edwards RH (2013) The function of alpha-synuclein. Neuron 79(6):1044–1066

    CAS  PubMed  Google Scholar 

  • Bendotti C, Marino M, Cheroni C et al (2012) Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog Neurobiol 97(2):101–126

    CAS  PubMed  Google Scholar 

  • Bernassola F, Chillemi G, Melino G (2019) HECT-type E3 ubiquitin ligases in cancer. Trends Biochem Sci 44(12):1057–1075

    CAS  PubMed  Google Scholar 

  • Bi M, Gladbach A, van Eersel J et al (2017) Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun 8(1):473

    PubMed  PubMed Central  Google Scholar 

  • Bittar A, Bhatt N, Kayed R (2020) Advances and considerations in AD tau-targeted immunotherapy. Neurobiol Dis 134:104707

    CAS  PubMed  Google Scholar 

  • Blokhuis AM, Groen EJ, Koppers M et al (2013) Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol 125(6):777–794

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boeynaems S, Alberti S, Fawzi NL et al (2018) Protein phase separation: a new phase in cell biology. Trends Cell Biol 28(6):420–435

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brummitt RK, Nesta DP, Chang L et al (2011) Nonnative aggregation of an IgG1 antibody in acidic conditions, part 2: nucleation and growth kinetics with competing growth mechanisms. J Pharm Sci 100(6):2104–2119

    CAS  PubMed  Google Scholar 

  • Buckley KM, Hess DL, Sazonova IY et al (2014) Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp Transl Stroke Med 6:8–8

    PubMed  PubMed Central  Google Scholar 

  • Buetow L, Huang DT (2016) Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol 17(10):626–642

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cabezas-Opazo FA, Vergara-Pulgar K, Perez MJ et al (2015) Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev 2015:509654

    PubMed  PubMed Central  Google Scholar 

  • Cadavid D, Mena H, Koeller K et al (2000) Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 59(9):768–773

    CAS  PubMed  Google Scholar 

  • Caldeira MV, Curcio M, Leal G et al (2013) Excitotoxic stimulation downregulates the ubiquitin-proteasome system through activation of NMDA receptors in cultured hippocampal neurons. Biochim Biophys Acta 1832(1):263–274

    CAS  PubMed  Google Scholar 

  • Carloni S, Girelli S, Scopa C et al (2010) Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 6(3):366–377

    CAS  PubMed  Google Scholar 

  • Catanese L, Tarsia J, Fisher M (2017) Acute ischemic stroke therapy overview. Circ Res 120(3):541–558

    CAS  PubMed  Google Scholar 

  • Cenini G, Voos W (2016) Role of mitochondrial protein quality control in oxidative stress-induced neurodegenerative diseases. Curr Alzheimer Res 13(2):164–173

    CAS  PubMed  Google Scholar 

  • Charidimou A, Gang Q, Werring DJ (2012) Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 83(2):124–137

    PubMed  Google Scholar 

  • Chauhan A, Sharma U, Jagannathan NR et al (2011) Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225(2):603–609

    CAS  PubMed  Google Scholar 

  • Chaytow H, Huang YT, Gillingwater TH et al (2018) The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci 75(21):3877–3894

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Jiang H (2019) Tau as a potential therapeutic target for ischemic stroke. Aging 11(24):12827–12843

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Guan T, Li C et al (2012) SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI). J Neuroinflamm 9:237

    Google Scholar 

  • Chung CY, Berson A, Kennerdell JR et al (2018) Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity. Nat Commun 9(1):4406

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  • Civelek M, Mehrkens JF, Carstens NM et al (2019) Inhibition of mitophagy decreases survival of Caenorhabditis elegans by increasing protein aggregation. Mol Cell Biochem 452(1–2):123–131

    CAS  PubMed  Google Scholar 

  • Clarke PG, Puyal J (2012) Autophagic cell death exists. Autophagy 8(6):867–869

    PubMed  PubMed Central  Google Scholar 

  • Cohen NR, Kayatekin C, Zitzewitz JA et al (2020) Friction-limited folding of disulfide-reduced monomeric SOD1. Biophys J 118(8):1992–2000

    CAS  PubMed  PubMed Central  Google Scholar 

  • Corraini P, Henderson VW, Ording AG et al (2017) Long-term risk of dementia among survivors of ischemic or hemorrhagic stroke. Stroke 48(1):180–186

    CAS  PubMed  Google Scholar 

  • Currais A, Fischer W, Maher P et al (2017) Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain. FASEB J 31(1):5–10

    CAS  PubMed  Google Scholar 

  • D'Andrea L, Simon-Moya M, Llorente B et al (2018) Interference with Clp protease impairs carotenoid accumulation during tomato fruit ripening. J Exp Bot 69(7):1557–1568

    CAS  PubMed  PubMed Central  Google Scholar 

  • David DC, Ollikainen N, Trinidad JC et al (2010) Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol 8(8):e1000450

    PubMed  PubMed Central  Google Scholar 

  • DeGracia DJ, Hu BR (2007) Irreversible translation arrest in the reperfused brain. J Cereb Blood Flow Metab 27(5):875–893

    CAS  PubMed  Google Scholar 

  • de Oliveira GAP, Cordeiro Y, Silva JL et al (2019) Liquid-liquid phase transitions and amyloid aggregation in proteins related to cancer and neurodegenerative diseases. Adv Protein Chem Struct Biol 118:289–331

    PubMed  Google Scholar 

  • Deng Y, Chen D, Gao F et al (2020) Silencing of long non-coding RNA GAS5 suppresses neuron cell apoptosis and nerve injury in ischemic stroke through inhibiting DNMT3B-dependent MAP4K4 methylation. Transl Stroke Res

  • Deshaies JE, Shkreta L, Moszczynski AJ et al (2018) TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain 141(5):1320–1333

    PubMed  PubMed Central  Google Scholar 

  • Deshpande J, Bergstedt K, Linden T et al (1992) Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death. Exp Brain Res 88(1):91–105

    CAS  PubMed  Google Scholar 

  • Di Carlo V, Grossi E, Laneve P et al (2013) TDP-43 regulates the microprocessor complex activity during in vitro neuronal differentiation. Mol Neurobiol 48(3):952–963

    PubMed  Google Scholar 

  • Ding X, Sun F, Chen J et al (2020) Amyloid-forming segment induces aggregation of FUS-LC domain from phase separation modulated by site-specific phosphorylation. J Mol Biol 432(2):467–483

    CAS  PubMed  Google Scholar 

  • Dolgin E (2018) What lava lamps and vinaigrette can teach us about cell biology. Nature 555(7696):300–302

    CAS  PubMed  Google Scholar 

  • Dong S, Maniar S, Manole MD et al (2018) Cerebral hypoperfusion and other shared brain pathologies in ischemic stroke and Alzheimer’s disease. Transl Stroke Res 9(3):238–250

    CAS  PubMed  Google Scholar 

  • Droppelmann CA, Campos-Melo D, Moszczynski AJ et al (2019) TDP-43 aggregation inside micronuclei reveals a potential mechanism for protein inclusion formation in ALS. Sci Rep 9(1):19928

    CAS  PubMed  PubMed Central  Google Scholar 

  • Filipe V, Kukrer B, Hawe A et al (2012) Transient molten globules and metastable aggregates induced by brief exposure of a monoclonal IgG to low pH. J Pharm Sci 101(7):2327–2339

    CAS  PubMed  Google Scholar 

  • Freedman RB, Desmond JL, Byrne LJ et al (2017) 'Something in the way she moves': the functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI). Biochim Biophys Acta Proteins Proteom 1865(11):1383–1394

    CAS  PubMed  Google Scholar 

  • Freeze WM, Bacskai BJ, Frosch MP et al (2019) Blood-brain barrier leakage and microvascular lesions in cerebral amyloid angiopathy. Stroke 50(2):328–335

    CAS  PubMed  PubMed Central  Google Scholar 

  • Galves M, Rathi R, Prag G et al (2019) Ubiquitin signaling and degradation of aggregate-prone proteins. Trends Biochem Sci 44(10):872–884

    CAS  PubMed  Google Scholar 

  • Gao YL, Wang N, Sun FR et al (2018) Tau in neurodegenerative disease. Ann Transl Med 6(10):175

    PubMed  PubMed Central  Google Scholar 

  • Ge P, Luo Y, Liu CL et al (2007) Protein aggregation and proteasome dysfunction after brain ischemia. Stroke 38(12):3230–3236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goulay R, Mena Romo L, Hol EM et al (2019) From stroke to dementia: a comprehensive review exposing tight interactions between stroke and amyloid-beta formation. Transl Stroke Res

  • Graham SH, Liu H (2017) Life and death in the trash heap: the ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia. Ageing Res Rev 34:30–38

    CAS  PubMed  Google Scholar 

  • Gregory RI, Yan KP, Amuthan G et al (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240

    CAS  PubMed  Google Scholar 

  • Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133(5):665–704

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gustot A, Gallea JI, Sarroukh R et al (2015) Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease. Biochem J 471(3):323–333

    CAS  PubMed  Google Scholar 

  • Haglund M, Passant U, Sjobeck M et al (2006) Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia. Int J Geriatr Psychiatry 21(7):681–687

    PubMed  Google Scholar 

  • Hankey GJ (2017) Stroke. Lancet 389(10069):641–654

    PubMed  Google Scholar 

  • Hatsuta H, Takao M, Nogami A et al (2019) Tau and TDP-43 accumulation of the basal nucleus of Meynert in individuals with cerebral lobar infarcts or hemorrhage. Acta Neuropathol Commun 7(1):49

    PubMed  PubMed Central  Google Scholar 

  • Hayashi T, Takada K, Matsuda M (1991) Changes in ubiquitin and ubiquitin-protein conjugates in the CA1 neurons after transient sublethal ischemia. Mol Chem Neuropathol 15(1):75–82

    CAS  PubMed  Google Scholar 

  • Hayashi T, Takada K, Matsuda M (1992) Post-transient ischemia increase in ubiquitin conjugates in the early reperfusion. NeuroReport 3(6):519–520

    CAS  PubMed  Google Scholar 

  • Hochrainer K (2018) Protein modifications with ubiquitin as response to cerebral ischemia-reperfusion injury. Transl Stroke Res 9(2):157–173

    CAS  PubMed  Google Scholar 

  • Hochrainer K, Jackman K, Anrather J et al (2012) Reperfusion rather than ischemia drives the formation of ubiquitin aggregates after middle cerebral artery occlusion. Stroke 43(8):2229–2235

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hochrainer K, Jackman K, Benakis C et al (2015) SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion. J Cereb Blood Flow Metab 35(1):1–5

    CAS  PubMed  Google Scholar 

  • Hoffmann A, Ettle B, Bruno A et al (2016) Alpha-synuclein activates BV2 microglia dependent on its aggregation state. Biochem Biophys Res Commun 479(4):881–886

    CAS  PubMed  Google Scholar 

  • Hu BR, Martone ME, Jones YZ et al (2000) Protein aggregation after transient cerebral ischemia. J Neurosci 20(9):3191–3199

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hu BR, Janelidze S, Ginsberg MD et al (2001) Protein aggregation after focal brain ischemia and reperfusion. J Cereb Blood Flow Metab 21(7):865–875

    CAS  PubMed  Google Scholar 

  • Huang JJ, Li XN, Liu WL et al (2019) Neutralizing mutations significantly inhibit amyloid formation by human prion protein and decrease its cytotoxicity. J Mol Biol

  • Junn E, Lee KW, Jeong BS et al (2009) Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci USA 106(31):13052–13057

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kahl A, Blanco I, Jackman K et al (2018) Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases. Sci Rep 8(1):2701

    PubMed  PubMed Central  Google Scholar 

  • Kaufman DM, Wu X, Scott BA et al (2017) Ageing and hypoxia cause protein aggregation in mitochondria. Cell Death Differ 24(10):1730–1738

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kent KP, Schroeder CE, Sharma C (2018) Solution pH jump during antibody and Fc-fusion protein thaw leads to increased aggregation. J Pharm Anal 8(5):302–306

    PubMed  Google Scholar 

  • Khalid MF, Damha MJ, Shuman S et al (2005) Structure-function analysis of yeast RNA debranching enzyme (Dbr1), a manganese-dependent phosphodiesterase. Nucleic Acids Res 33(19):6349–6360

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kia A, McAvoy K, Krishnamurthy K et al (2018) Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha. Glia 66(5):1016–1033

    PubMed  PubMed Central  Google Scholar 

  • Kim T, Mehta SL, Kaimal B et al (2016) Poststroke induction of alpha-synuclein mediates ischemic brain damage. J Neurosci 36(26):7055–7065

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim T, Mehta SL, Morris-Blanco KC et al (2018) The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing alpha-synuclein. Sci Signal 11(560):eaat4285

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kirino T, Tamura A, Sano K (1984) Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 64(2):139–147

    CAS  PubMed  Google Scholar 

  • Kovalska M, Tothova B, Kovalska L et al (2018) Association of induced hyperhomocysteinemia with Alzheimer's disease-like neurodegeneration in rat cortical neurons after global ischemia-reperfusion injury. Neurochem Res 43(9):1766–1778

    CAS  PubMed  Google Scholar 

  • Kwon YT, Ciechanover A (2017) The Ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem Sci 42(11):873–886

    CAS  PubMed  Google Scholar 

  • Lam TI, Brennan-Minnella AM, Won SJ et al (2013) Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase. Proc Natl Acad Sci USA 110(46):E4362–4368

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lashuel HA, Overk CR, Oueslati A et al (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14(1):38–48

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SO, Cho K, Cho S et al (2010) Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation. EMBO J 29(2):363–375

    CAS  PubMed  Google Scholar 

  • Levy E, El Banna N, Baille D et al (2019) Causative links between protein aggregation and oxidative stress: a review. Int J Mol Sci 20(16):3896

    CAS  PubMed Central  Google Scholar 

  • Li Q, Zhang T, Wang J et al (2014) Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke. Biochem Biophys Res Commun 444(2):182–188

    CAS  PubMed  Google Scholar 

  • Li Y, Luo Y, Luo T et al (2017) Trehalose Inhibits protein aggregation caused by transient ischemic insults through preservation of proteasome activity, not via induction of autophagy. Mol Neurobiol 54(9):6857–6869

    CAS  PubMed  Google Scholar 

  • Li G, Morris-Blanco KC, Lopez MS et al (2018a) Impact of microRNAs on ischemic stroke: From pre- to post-disease. Prog Neurobiol 163–164:59–78

    PubMed  Google Scholar 

  • Li P, Stetler RA, Leak RK et al (2018b) Oxidative stress and DNA damage after cerebral ischemia: potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134(Pt B):208–217

    CAS  PubMed  Google Scholar 

  • Liang J, Yao J, Wang G et al (2012) Ischemic postconditioning protects neuronal death caused by cerebral ischemia and reperfusion via attenuating protein aggregation. Int J Med Sci 9(10):923–932

    PubMed  PubMed Central  Google Scholar 

  • Liang Z, Wu G, Fan C et al (2016) The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. Prog Neurobiol 137:1–16

    CAS  PubMed  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795

    CAS  PubMed  Google Scholar 

  • Lin Y, Protter DS, Rosen MK et al (2015) Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol Cell 60(2):208–219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu C, Chen S, Kamme F et al (2005a) Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. Neuroscience 134(1):69–80

    CAS  PubMed  Google Scholar 

  • Liu CL, Ge P, Zhang F et al (2005b) Co-translational protein aggregation after transient cerebral ischemia. Neuroscience 134(4):1273–1284

    CAS  PubMed  Google Scholar 

  • Liu F, Lu J, Manaenko A et al (2018) Mitochondria in ischemic stroke: new insight and implications. Aging Dis 9(5):924–937

    PubMed  PubMed Central  Google Scholar 

  • Luo T, Park Y, Sun X et al (2013) Protein misfolding, aggregation, and autophagy after brain ischemia. Transl Stroke Res 4(6):581–588

    CAS  PubMed  Google Scholar 

  • Lyles MM, Gilbert HF (1991) Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer. Biochemistry 30(3):613–619

    CAS  PubMed  Google Scholar 

  • Magalhaes S, Trindade D, Martins T et al (2020) Monitoring plasma protein aggregation during aging using conformation-specific antibodies and FTIR spectroscopy. Clin Chim Acta 502:25–33

    CAS  PubMed  Google Scholar 

  • Martin DD, Ladha S, Ehrnhoefer DE et al (2015) Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci 38(1):26–35

    CAS  PubMed  Google Scholar 

  • McMillan KJ, Murray TK, Bengoa-Vergniory N et al (2017) Loss of MicroRNA-7 regulation leads to alpha-synuclein accumulation and dopaminergic neuronal loss in vivo. Mol Ther 25(10):2404–2414

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mehta SL, Pandi G, Vemuganti R (2017) Circular RNA expression profiles alter significantly in mouse brain after transient focal ischemia. Stroke 48(9):2541–2548

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mitrea DM, Kriwacki RW (2016) Phase separation in biology; functional organization of a higher order. Cell Commun Signal 14:1

    PubMed  PubMed Central  Google Scholar 

  • Murphy S (2000) Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia 29(1):1–13

    CAS  PubMed  Google Scholar 

  • Nguyen TM, Kabotyanski EB, Reineke LC et al (2019) The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis. Nucleic Acids Res

  • Pase MP, Himali JJ, Aparicio HJ et al (2019) Plasma total-tau as a biomarker of stroke risk in the community. Ann Neurol 86(3):463–467

    CAS  PubMed  PubMed Central  Google Scholar 

  • Patel A, Malinovska L, Saha S et al (2017) ATP as a biological hydrotrope. Science 356(6339):753–756

    CAS  PubMed  Google Scholar 

  • Pavel M, Imarisio S, Menzies FM et al (2016) CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat Commun 7:13821

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pluta R (2007) Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer's disease brain. Curr Neurovasc Res 4(2):121–129

    CAS  PubMed  Google Scholar 

  • Pluta R, Ulamek M, Jablonski M (2009) Alzheimer's mechanisms in ischemic brain degeneration. Anat Rec 292(12):1863–1881

    CAS  Google Scholar 

  • Pluta R, Ulamek M, Jablonski M (2010) Consideration of the ischaemic basis and treatment of Alzheimer's disease. Folia Neuropathol 48(1):11–26

    CAS  PubMed  Google Scholar 

  • Pluta R, Bogucka-Kocka A, Ulamek-Koziol M et al (2018) Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer's phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer's disease. Pharmacol Rep 70(5):881–884

    CAS  PubMed  Google Scholar 

  • Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138(Suppl 1):95–111

    CAS  PubMed  Google Scholar 

  • Roman SG, Chebotareva NA, Kurganov BI (2017) Anti-aggregation activity of small heat shock proteins under crowded conditions. Int J Biol Macromol 100:97–103

    CAS  PubMed  Google Scholar 

  • Rother J (2008) Neuroprotection does not work! Stroke 39(2):523–524

    PubMed  Google Scholar 

  • Ryan VH, Dignon GL, Zerze GH et al (2018) Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol Cell 69(3):465–479

    CAS  PubMed  PubMed Central  Google Scholar 

  • Santos J, Iglesias V, Santos-Suarez J et al (2020) pH-dependent aggregation in intrinsically disordered proteins is determined by charge and lipophilicity. Cells 9(1):145

    CAS  PubMed Central  Google Scholar 

  • Sato Y, Tsuchiya H, Yamagata A et al (2019) Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4. Nat Commun 10(1):5708

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schaser AJ, Osterberg VR, Dent SE et al (2019) Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep 9(1):10919

    PubMed  PubMed Central  Google Scholar 

  • Schwartz AL, Ciechanover A (2009) Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 49:73–96

    CAS  PubMed  Google Scholar 

  • Shorter J (2019) Phase separation of RNA-binding proteins in physiology and disease: an introduction to the JBC Reviews thematic series. J Biol Chem 294(18):7113–7114

    CAS  PubMed  PubMed Central  Google Scholar 

  • Silva MC, Amaral MD, Morimoto RI (2013) Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response. PLoS Genet 9(8):e1003711

    PubMed  PubMed Central  Google Scholar 

  • Skamris T, Tian X, Thorolfsson M et al (2016) Monoclonal antibodies follow distinct aggregation pathways during production-relevant acidic incubation and neutralization. Pharm Res 33(3):716–728

    CAS  PubMed  Google Scholar 

  • Soontornniyomkij V, Lynch MD, Mermash S et al (2010) Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 20(2):459–467

    PubMed  Google Scholar 

  • Stoica G, Lungu G, Bjorklund NL et al (2012) Potential role of alpha-synuclein in neurodegeneration: studies in a rat animal model. J Neurochem 122(4):812–822

    CAS  PubMed  Google Scholar 

  • Stonesifer C, Corey S, Ghanekar S et al (2017) Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 158:94–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suh J, Im DS, Moon GJ et al (2010) Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing. J Neurochem 114(1):160–170

    CAS  PubMed  Google Scholar 

  • Sun Z, Diaz Z, Fang X et al (2011) Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9(4):e1000614

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swatek KN, Komander D (2016) Ubiquitin modifications. Cell Res 26(4):399–422

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tai HC, Besche H, Goldberg AL et al (2010) Characterization of the brain 26S proteasome and its interacting proteins. Front Mol Neurosci 3:12

    PubMed  PubMed Central  Google Scholar 

  • Tokuda E, Furukawa Y (2017) Abnormal protein oligomers for neurodegeneration. Oncotarget 8(25):39943–39944

    PubMed  PubMed Central  Google Scholar 

  • Toldo S, Severino A, Abbate A et al (2011) The role of PDI as a survival factor in cardiomyocyte ischemia. Methods Enzymol 489:47–65

    CAS  PubMed  Google Scholar 

  • Tsuiji H, Iguchi Y, Furuya A et al (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5(2):221–234

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vales-Montero M, Garcia-Pastor A, Iglesias-Mohedano AM et al (2019) Cerebral amyloid angiopathy-related transient focal neurological episodes: a transient ischemic attack mimic with an increased risk of intracranial hemorrhage. J Neurol Sci 406:116452

    PubMed  Google Scholar 

  • Vijayan M, Reddy PH (2016) Stroke, vascular dementia, and Alzheimer's disease: molecular links. J Alzheimers Dis 54(2):427–443

    PubMed  PubMed Central  Google Scholar 

  • Wang W, Roberts CJ (2018) Protein aggregation—mechanisms, detection, and control. Int J Pharm 550(1–2):251–268

    CAS  PubMed  Google Scholar 

  • Wang P, Shao BZ, Deng Z et al (2018) Autophagy in ischemic stroke. Prog Neurobiol 163–164:98–117

    PubMed  Google Scholar 

  • Wang Y, Tian D, Wei C et al (2019) Propofol attenuates alpha-synuclein aggregation and neuronal damage in a mouse model of ischemic stroke. Neurosci Bull

  • Wegmann S, Eftekharzadeh B, Tepper K et al (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37(7):e98049

    PubMed  PubMed Central  Google Scholar 

  • Weids AJ, Grant CM (2014) The yeast peroxiredoxin Tsa1 protects against protein-aggregate-induced oxidative stress. J Cell Sci 127(Pt 6):1327–1335

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wen Y, Yang SH, Liu R et al (2007) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772(4):473–483

    CAS  PubMed  Google Scholar 

  • Wolozin B (2019) The evolution of phase-separated TDP-43 in stress. Neuron 102(2):265–267

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wright RHG, Le Dily F, Beato M (2019) ATP, Mg(2+), nuclear phase separation, and genome accessibility. Trends Biochem Sci 44(7):565–574

    CAS  PubMed  Google Scholar 

  • Yamazaki T, Chen S, Yu Y et al (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2(4):799–806

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yau R, Rape M (2016) The increasing complexity of the ubiquitin code. Nat Cell Biol 18(6):579–586

    CAS  PubMed  Google Scholar 

  • Yedlapudi D, Xu L, Luo D et al (2019) Targeting alpha synuclein and amyloid beta by a multifunctional, brain-penetrant dopamine D2/D3 agonist D-520: potential therapeutic application in Parkinson's disease with dementia. Sci Rep 9(1):19648

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zang J, Lu D, Xu A (2020) The interaction of circRNAs and RNA binding proteins: an important part of circRNA maintenance and function. J Neurosci Res 98(1):87–97

    CAS  PubMed  Google Scholar 

  • Zerna C, Thomalla G, Campbell BCV et al (2018) Current practice and future directions in the diagnosis and acute treatment of ischaemic stroke. Lancet 392(10154):1247–1256

    PubMed  Google Scholar 

  • Zhang F, Liu CL, Hu BR (2006) Irreversible aggregation of protein synthesis machinery after focal brain ischemia. J Neurochem 98(1):102–112

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HP, Yuan LB, Zhao RN et al (2010) Isoflurane preconditioning induces neuroprotection by attenuating ubiquitin-conjugated protein aggregation in a mouse model of transient global cerebral ischemia. Anesth Analg 111(2):506–514

    CAS  PubMed  Google Scholar 

  • Zhang X, Yan H, Yuan Y et al (2013) Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9(9):1321–1333

    CAS  PubMed  Google Scholar 

  • Zhang X, Yuan Y, Jiang L et al (2014) Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy 10(10):1801–1813

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HY, Wang ZG, Lu XH et al (2015) Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases. Mol Neurobiol 51(3):1343–1352

    CAS  PubMed  Google Scholar 

  • Zhang X, Wesen E, Kumar R et al (2020) Correlation between cellular uptake and cytotoxicity of fragmented alpha-synuclein amyloid fibrils suggests intracellular basis for toxicity. ACS Chem Neurosci 11(3):233–241

    CAS  PubMed  Google Scholar 

  • Zhou Y, Liu S, Liu G et al (2013) ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet 9(10):e1003895

    PubMed  PubMed Central  Google Scholar 

  • Zhou J, Yu JT, Wang HF et al (2015) Association between stroke and Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis 43(2):479–489

    PubMed  Google Scholar 

  • Zhou Z, Lu J, Liu WW et al (2018) Advances in stroke pharmacology. Pharmacol Ther 191:23–42

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by Grants from 2019 PhD Research Startup Fund of Affiliated Hospital of Yangzhou University (No. BS2019DLF).

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China

    Shusheng Wu

  2. Department of Laboratory Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China

    Longfei Du

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  1. Shusheng Wu
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  2. Longfei Du
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SW wrote the manuscript, Dr. LD provided constructive comments.

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Correspondence to Shusheng Wu.

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Wu, S., Du, L. Protein Aggregation in the Pathogenesis of Ischemic Stroke. Cell Mol Neurobiol 41, 1183–1194 (2021). https://doi.org/10.1007/s10571-020-00899-y

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