Liquid-liquid phase separation in Alzheimer's disease.

Smith JJ, Aitchison JD (2013) Peroxisomes take shape. Nat Rev Mol Cell Biol 14(12):803–817. https://doi.org/10.1038/nrm3700

doi: 10.1038/nrm3700 pubmed: 24263361 pmcid: 4060825

Mao YS, Zhang B, Spector DL (2011) Biogenesis and function of nuclear bodies. Trends Genet 27(8):295–306. https://doi.org/10.1016/j.tig.2011.05.006

Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529(7586):326–335. https://doi.org/10.1038/nature17041

doi: 10.1038/nature17041 pubmed: 26791723

Banani SF, Lee HO, Hyman AA, Rosen MK (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18(5):285–298. https://doi.org/10.1038/nrm.2017.7

doi: 10.1038/nrm.2017.7 pubmed: 28225081 pmcid: 7434221

Zhang H, Elbaum-Garfinkle S, Langdon EM, Taylor N, Occhipinti P, Bridges AA, Brangwynne CP, Gladfelter AS (2015) RNA controls PolyQ protein phase transitions. Mol Cell 60(2):220–230. https://doi.org/10.1016/j.molcel.2015.09.017

doi: 10.1016/j.molcel.2015.09.017 pubmed: 26474065 pmcid: 5221516

Li P, Banjade S, Cheng HC, Kim S, Chen B, Guo L, Llaguno M, Hollingsworth JV, King DS, Banani SF et al (2012) Phase transitions in the assembly of multivalent signalling proteins. Nature 483(7389):336–340. https://doi.org/10.1038/nature10879

doi: 10.1038/nature10879 pubmed: 22398450 pmcid: 3343696

Jones N, Blasutig IM, Eremina V, Ruston JM, Bladt F, Li H, Huang H, Larose L, Li SS, Takano T et al (2006) Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 440(7085):818–823. https://doi.org/10.1038/nature04662

doi: 10.1038/nature04662 pubmed: 16525419

Banjade S, Rosen MK (2014) Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3. https://doi.org/10.7554/eLife.04123

Yang P, Mathieu C, Kolaitis RM, Zhang P, Messing J, Yurtsever U, Yang Z, Wu J, Li Y, Pan Q et al (2020) G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell 181(2):325–45.e28. https://doi.org/10.1016/j.cell.2020.03.046

doi: 10.1016/j.cell.2020.03.046 pubmed: 32302571 pmcid: 7448383

Decker CJ, Parker R (2012) P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb Perspect Biol 4(9):a012286. https://doi.org/10.1101/cshperspect.a012286

doi: 10.1101/cshperspect.a012286 pubmed: 22763747 pmcid: 3428773

Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C, Gharakhani J, Jülicher F, Hyman AA (2009) Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324(5935):1729–1732. https://doi.org/10.1126/science.1172046

doi: 10.1126/science.1172046 pubmed: 19460965

Nizami Z, Deryusheva S, Gall JG (2010) The Cajal body and histone locus body. Cold Spring Harb Perspect Biol 2(7):a000653. https://doi.org/10.1101/cshperspect.a000653

doi: 10.1101/cshperspect.a000653 pubmed: 20504965 pmcid: 2890199

Shin Y, Brangwynne CP (2017) Liquid phase condensation in cell physiology and disease. Science 357(6357). https://doi.org/10.1126/science.aaf4382

Mehta S, Zhang J (2022) Liquid-liquid phase separation drives cellular function and dysfunction in cancer. Nat Rev Cancer 22(4):239–252. https://doi.org/10.1038/s41568-022-00444-7

doi: 10.1038/s41568-022-00444-7 pubmed: 35149762 pmcid: 10036213

Wang J, Choi JM, Holehouse AS, Lee HO, Zhang X, Jahnel M, Maharana S, Lemaitre R, Pozniakovsky A, Drechsel D et al (2018) A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174(3):688–99.e16. https://doi.org/10.1016/j.cell.2018.06.006

doi: 10.1016/j.cell.2018.06.006 pubmed: 29961577 pmcid: 6063760

Zhang H, Ji X, Li P, Liu C, Lou J, Wang Z, Wen W, Xiao Y, Zhang M, Zhu X (2020) Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases. Sci China Life Sci 63(7):953–985. https://doi.org/10.1007/s11427-020-1702-x

Tong X, Tang R, Xu J, Wang W, Zhao Y, Yu X, Shi S (2022) Liquid-liquid phase separation in tumor biology. Signal Transduct Target Ther 7(1):221. https://doi.org/10.1038/s41392-022-01076-x

doi: 10.1038/s41392-022-01076-x pubmed: 35803926 pmcid: 9270353

Wang B, Zhang L, Dai T, Qin Z, Lu H, Zhang L, Zhou F (2021) Liquid-liquid phase separation in human health and diseases. Signal Transduct Target Ther 6(1):290. https://doi.org/10.1038/s41392-021-00678-1

doi: 10.1038/s41392-021-00678-1 pubmed: 34334791 pmcid: 8326283

Shin Y, Chang YC, Lee DSW, Berry J, Sanders DW, Ronceray P, Wingreen NS, Haataja M, Brangwynne CP (2018) Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175(6):1481–91.e13. https://doi.org/10.1016/j.cell.2018.10.057

doi: 10.1016/j.cell.2018.10.057 pubmed: 30500535 pmcid: 6724728

Quinodoz SA, Ollikainen N, Tabak B, Palla A, Schmidt JM, Detmar E, Lai MM, Shishkin AA, Bhat P, Takei Y et al (2018) Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus. Cell 174(3):744–57.e24. https://doi.org/10.1016/j.cell.2018.05.024

doi: 10.1016/j.cell.2018.05.024 pubmed: 29887377 pmcid: 6548320

Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH (2017) Phase separation drives heterochromatin domain formation. Nature 547(7662):241–245. https://doi.org/10.1038/nature22989

doi: 10.1038/nature22989 pubmed: 28636597 pmcid: 6022742

Pessina F, Giavazzi F, Yin Y, Gioia U, Vitelli V, Galbiati A, Barozzi S, Garre M, Oldani A, Flaus A et al (2019) Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors. Nat Cell Biol 21(10):1286–1299. https://doi.org/10.1038/s41556-019-0392-4

doi: 10.1038/s41556-019-0392-4 pubmed: 31570834 pmcid: 6859070

Mirza-Aghazadeh-Attari M, Mohammadzadeh A, Yousefi B, Mihanfar A, Karimian A, Majidinia M (2019) 53BP1: a key player of DNA damage response with critical functions in cancer. DNA Repair 73:110–119. https://doi.org/10.1016/j.dnarep.2018.11.008

doi: 10.1016/j.dnarep.2018.11.008 pubmed: 30497961

Lu H, Yu D, Hansen AS, Ganguly S, Liu R, Heckert A, Darzacq X, Zhou Q (2018) Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature 558(7709):318–323. https://doi.org/10.1038/s41586-018-0174-3

doi: 10.1038/s41586-018-0174-3 pubmed: 29849146 pmcid: 6475116

Sabari BR, Dall’Agnese A, Boija A, Klein IA, Coffey EL, Shrinivas K, Abraham BJ, Hannett NM, Zamudio AV, Manteiga JC et al (2018) Coactivator condensation at super-enhancers links phase separation and gene control. Science 361(6400). https://doi.org/10.1126/science.aar3958

Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD (2016) Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352(6285):595–599. https://doi.org/10.1126/science.aad9964

doi: 10.1126/science.aad9964 pubmed: 27056844 pmcid: 4892427

Su Q, Mehta S, Zhang J (2021) Liquid-liquid phase separation: Orchestrating cell signaling through time and space. Mol Cell 81(20):4137–4146. https://doi.org/10.1016/j.molcel.2021.09.010

doi: 10.1016/j.molcel.2021.09.010 pubmed: 34619090 pmcid: 8541918

Pereira B, Billaud M, Almeida R (2017) RNA-binding proteins in cancer: old players and new actors. Trends in cancer 3(7):506–528. https://doi.org/10.1016/j.trecan.2017.05.003

doi: 10.1016/j.trecan.2017.05.003 pubmed: 28718405

Kang JY, Wen Z, Pan D, Zhang Y, Li Q, Zhong A, Yu X, Wu YC, Chen Y, Zhang X et al (2022) LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs. Science 377(6607):eabj6647. https://doi.org/10.1126/science.abj6647

Xie J, He H, Kong W, Li Z, Gao Z, Xie D, Sun L, Fan X, Jiang X, Zheng Q et al (2022) Targeting androgen receptor phase separation to overcome antiandrogen resistance. Nat Chem Biol. https://doi.org/10.1038/s41589-022-01151-y

doi: 10.1038/s41589-022-01151-y pubmed: 36229685

Iserman C, Roden CA, Boerneke MA, Sealfon RSG, McLaughlin GA, Jungreis I, Fritch EJ, Hou YJ, Ekena J, Weidmann CA et al (2020) Genomic RNA elements drive phase separation of the SARS-CoV-2 nucleocapsid. Mol Cell 80(6):1078–91.e6. https://doi.org/10.1016/j.molcel.2020.11.041

doi: 10.1016/j.molcel.2020.11.041 pubmed: 33290746 pmcid: 7691212

Chen H, Cui Y, Han X, Hu W, Sun M, Zhang Y, Wang PH, Song G, Chen W, Lou J (2020) Liquid-liquid phase separation by SARS-CoV-2 nucleocapsid protein and RNA. Cell Res 30(12):1143–1145. https://doi.org/10.1038/s41422-020-00408-2

doi: 10.1038/s41422-020-00408-2 pubmed: 32901111

Cai D, Liu Z, Lippincott-Schwartz J (2021) Biomolecular condensates and their links to cancer progression. Trends Biochem Sci 46(7):535–549. https://doi.org/10.1016/j.tibs.2021.01.002

doi: 10.1016/j.tibs.2021.01.002 pubmed: 33579564

Boija A, Klein IA, Young RA (2021) Biomolecular condensates and cancer Cancer cell 39(2):174–192. https://doi.org/10.1016/j.ccell.2020.12.003

doi: 10.1016/j.ccell.2020.12.003 pubmed: 33417833

Hodson R (2018) Alzheimer’s disease. Nature 559(7715):S1. https://doi.org/10.1038/d41586-018-05717-6

doi: 10.1038/d41586-018-05717-6 pubmed: 30046078

Masters CL, Beyreuther K (1998) Alzheimer’s disease BMJ (Clinical research ed) 316(7129):446–448. https://doi.org/10.1136/bmj.316.7129.446

doi: 10.1136/bmj.316.7129.446 pubmed: 9492674

Steel K (2010) Alzheimer’s disease. N Engl J Med 362(19):1844–1845. https://doi.org/10.1056/NEJMc1002323

doi: 10.1056/NEJMc1002323 pubmed: 20468086

Vagnucci AH Jr, Li WW (2003) Alzheimer’s disease and angiogenesis. Lancet (London, England) 361(9357):605–608. https://doi.org/10.1016/s0140-6736(03)12521-4

doi: 10.1016/s0140-6736(03)12521-4 pubmed: 12598159

Fiandaca MS, Mapstone ME, Cheema AK, Federoff HJ (2014) The critical need for defining preclinical biomarkers in Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 10(3 Suppl):S196-212. https://doi.org/10.1016/j.jalz.2014.04.015

Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, Rabinovici GD, Schott JM, Jones DT, Murray ME (2021) New insights into atypical Alzheimer’s disease in the era of biomarkers. The Lancet Neurology 20(3):222–234. https://doi.org/10.1016/s1474-4422(20)30440-3

doi: 10.1016/s1474-4422(20)30440-3 pubmed: 33609479 pmcid: 8056394

Pasinetti GM (2015) Towards prevention and therapy of Alzheimer’s disease. Mol Aspects Med 43–44:1–2. https://doi.org/10.1016/j.mam.2015.09.001

doi: 10.1016/j.mam.2015.09.001 pubmed: 26449935

Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, Senda K, Murayama S, Ishii K, Takao M et al (2015) Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 11(8):964–974. https://doi.org/10.1016/j.jalz.2015.02.004

Villemagne VL, Doré V, Bourgeat P, Burnham SC, Laws S, Salvado O, Masters CL, Rowe CC (2017) Aβ-amyloid and tau imaging in dementia. Semin Nucl Med 47(1):75–88. https://doi.org/10.1053/j.semnuclmed.2016.09.006

doi: 10.1053/j.semnuclmed.2016.09.006 pubmed: 27987560

Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 7(3):280–292. https://doi.org/10.1016/j.jalz.2011.03.003

Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. The Lancet Neurology 13(6):614–629. https://doi.org/10.1016/s1474-4422(14)70090-0

Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K et al (2016) Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 12(3):292–323. https://doi.org/10.1016/j.jalz.2016.02.002

Lin Y, Protter DS, Rosen MK, Parker R (2015) Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol Cell 60(2):208–219. https://doi.org/10.1016/j.molcel.2015.08.018

doi: 10.1016/j.molcel.2015.08.018 pubmed: 26412307 pmcid: 4609299

Strang KH, Golde TE, Giasson BI (2019) MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest 99(7):912–28. https://doi.org/10.1038/s41374-019-0197-x

Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8(2):393–399. https://doi.org/10.1002/j.1460-2075.1989.tb03390.x

doi: 10.1002/j.1460-2075.1989.tb03390.x pubmed: 2498079 pmcid: 400819

Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9):663–672. https://doi.org/10.1038/nrn2194

doi: 10.1038/nrn2194 pubmed: 17684513

Iqbal K, Liu F, Gong CX (2016) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12(1):15–27. https://doi.org/10.1038/nrneurol.2015.225

doi: 10.1038/nrneurol.2015.225 pubmed: 26635213

Brunden KR, Trojanowski JQ, Lee VM (2009) Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov 8(10):783–793. https://doi.org/10.1038/nrd2959

doi: 10.1038/nrd2959 pubmed: 19794442 pmcid: 2787232

Uversky VN (2017) Protein intrinsic disorder-based liquid-liquid phase transitions in biological systems: complex coacervates and membrane-less organelles. Adv Colloid Interface Sci 239:97–114. https://doi.org/10.1016/j.cis.2016.05.012

doi: 10.1016/j.cis.2016.05.012 pubmed: 27291647

Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA (2017) Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep 20(10):2304–2312. https://doi.org/10.1016/j.celrep.2017.08.042

doi: 10.1016/j.celrep.2017.08.042 pubmed: 28877466 pmcid: 5828996

Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C et al (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37(7). https://doi.org/10.15252/embj.201798049

Savastano A, Flores D, Kadavath H, Biernat J, Mandelkow E, Zweckstetter M (2021) Disease-associated tau phosphorylation hinders tubulin assembly within tau condensates. Angew Chem Int Ed Engl 60(2):726–730. https://doi.org/10.1002/anie.202011157

doi: 10.1002/anie.202011157 pubmed: 33017094

Kanaan NM, Hamel C, Grabinski T, Combs B (2020) Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat Commun 11(1):2809. https://doi.org/10.1038/s41467-020-16580-3

doi: 10.1038/s41467-020-16580-3 pubmed: 32499559 pmcid: 7272632

Lin Y, Fichou Y, Zeng Z, Hu NY, Han S (2020) Electrostatically driven complex coacervation and amyloid aggregation of tau are independent processes with overlapping conditions. ACS Chem Neurosci 11(4):615–627. https://doi.org/10.1021/acschemneuro.9b00627

doi: 10.1021/acschemneuro.9b00627 pubmed: 31971365

Boyko S, Surewicz WK (2022) Tau liquid-liquid phase separation in neurodegenerative diseases. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2022.01.011

doi: 10.1016/j.tcb.2022.01.011 pubmed: 35181198 pmcid: 9189016

Ainani H, Bouchmaa N, Ben Mrid R, El Fatimy R (2023) Liquid-liquid phase separation of protein tau: an emerging process in Alzheimer’s disease pathogenesis. Neurobiol Dis 178:106011. https://doi.org/10.1016/j.nbd.2023.106011

doi: 10.1016/j.nbd.2023.106011 pubmed: 36702317

Zeng Y, Yang J, Zhang B, Gao M, Su Z, Huang Y (2021) The structure and phase of tau: from monomer to amyloid filament. Cell Mol Life Sci 78(5):1873–1886. https://doi.org/10.1007/s00018-020-03681-x

Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S (2017) RNA stores tau reversibly in complex coacervates. PLoS Biol 15(7):e2002183. https://doi.org/10.1371/journal.pbio.2002183

doi: 10.1371/journal.pbio.2002183 pubmed: 28683104 pmcid: 5500003

Boyko S, Surewicz K, Surewicz WK (2020) Regulatory mechanisms of tau protein fibrillation under the conditions of liquid-liquid phase separation. Proc Natl Acad Sci USA 117(50):31882–31890. https://doi.org/10.1073/pnas.2012460117

doi: 10.1073/pnas.2012460117 pubmed: 33262278 pmcid: 7749306

Barnham K, Masters C, Bush A (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205–214. https://doi.org/10.1038/nrd1330

Bolognin S, Drago D, Messori L, Zatta P (2009) Chelation therapy for neurodegenerative diseases. Med Res Rev 29(4):547–570. https://doi.org/10.1002/med.20148

doi: 10.1002/med.20148 pubmed: 19177468

Bonda D, Lee H, Blair J, Zhu X, Perry G, Smith M (2011) Role of metal dyshomeostasis in Alzheimer’s disease. Metallomics 3(3):267–270. https://doi.org/10.1039/c0mt00074d

Bush A, Tanzi R (2008) Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5(3):421–432. https://doi.org/10.1016/j.nurt.2008.05.001

DeToma AS, Salamekh S, Ramamoorthy A, Lim MH (2012) Misfolded proteins in Alzheimer’s disease and type II diabetes. Chem Soc Rev 41(2):608–621. https://doi.org/10.1039/c1cs15112f

doi: 10.1039/c1cs15112f pubmed: 21818468

Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev 106(6):1995–2044. https://doi.org/10.1021/cr040410w

doi: 10.1021/cr040410w pubmed: 16771441

Rauk A (2009) The chemistry of Alzheimer’s disease. Chem Soc Rev 38(9):2698–2715. https://doi.org/10.1039/b807980n

doi: 10.1039/b807980n pubmed: 19690748

Scott L, Orvig C (2009) Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease. Chem Rev 109(10):4885–4910. https://doi.org/10.1021/cr9000176

doi: 10.1021/cr9000176 pubmed: 19637926

Zatta P, Drago D, Bolognin S, Sensi S (2009) Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci 30(7):346–355. https://doi.org/10.1016/j.tips.2009.05.002

doi: 10.1016/j.tips.2009.05.002 pubmed: 19540003

Liu Y, Nguyen M, Robert A, Meunier B (2019) Metal ions in Alzheimer’s disease: a key role or not? Acc Chem Res 52(7):2026–2035. https://doi.org/10.1021/acs.accounts.9b00248

doi: 10.1021/acs.accounts.9b00248 pubmed: 31274278

Wang L, Yin YL, Liu XZ, Shen P, Zheng YG, Lan XR, Lu CB, Wang JZ (2020) Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Translational neurodegeneration 9:10. https://doi.org/10.1186/s40035-020-00189-z

doi: 10.1186/s40035-020-00189-z pubmed: 32266063 pmcid: 7119290

Wang P, Wang ZY (2017) Metal ions influx is a double edged sword for the pathogenesis of Alzheimer’s disease. Ageing Res Rev 35:265–290. https://doi.org/10.1016/j.arr.2016.10.003

doi: 10.1016/j.arr.2016.10.003 pubmed: 27829171

Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, Wang ZY (2013) Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 62(2):165–172. https://doi.org/10.1016/j.neuint.2012.12.005

doi: 10.1016/j.neuint.2012.12.005 pubmed: 23262393

Voss K, Harris C, Ralle M, Duffy M, Murchison C, Quinn JF (2014) Modulation of tau phosphorylation by environmental copper. Transl Neurodegener 3(1):24. https://doi.org/10.1186/2047-9158-3-24

Xiong Y, Jing XP, Zhou XW, Wang XL, Yang Y, Sun XY, Qiu M, Cao FY, Lu YM, Liu R et al (2013) Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiol Aging 34(3):745–756. https://doi.org/10.1016/j.neurobiolaging.2012.07.003

doi: 10.1016/j.neurobiolaging.2012.07.003 pubmed: 22892311

Li XG, Hong XY, Wang YL, Zhang SJ, Zhang JF, Li XC, Liu YC, Sun DS, Feng Q, Ye JW et al (2019) Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression. EMBO Rep 20(6). https://doi.org/10.15252/embr.201847202

Liu ZC, Chu J, Lin L, Song J, Ning LN, Luo HB, Yang SS, Shi Y, Wang Q, Qu N et al (2016) SIL1 rescued Bip elevation-related tau hyperphosphorylation in ER stress. Mol Neurobiol 53(2):983–994. https://doi.org/10.1007/s12035-014-9039-4

doi: 10.1007/s12035-014-9039-4 pubmed: 25575678

Rane JS, Kumari A, Panda D (2020) The acetyl mimicking mutation, K274Q in tau, enhances the metal binding affinity of tau and reduces the ability of tau to protect DNA. ACS Chem Neurosci 11(3):291–303. https://doi.org/10.1021/acschemneuro.9b00455

doi: 10.1021/acschemneuro.9b00455 pubmed: 31886644

Gao YY, Zhong T, Wang LQ, Zhang N, Zeng Y, Hu JY, Dang HB, Chen J, Liang Y (2022) Zinc enhances liquid-liquid phase separation of Tau protein and aggravates mitochondrial damages in cells. Int J Biol Macromol 209(Pt A):703–715. https://doi.org/10.1016/j.ijbiomac.2022.04.034

doi: 10.1016/j.ijbiomac.2022.04.034 pubmed: 35405154

Singh V, Xu L, Boyko S, Surewicz K, Surewicz WK (2020) Zinc promotes liquid-liquid phase separation of tau protein. J Biol Chem 295(18):5850–5856. https://doi.org/10.1074/jbc.AC120.013166

doi: 10.1074/jbc.AC120.013166 pubmed: 32229582 pmcid: 7196643

Yatoui D, Tsvetkov PO, La Rocca R, Baksheeva VE, Allegro D, Breuzard G, Ferracci G, Byrne D, Devred F (2022) Binding of two zinc ions promotes liquid-liquid phase separation of Tau. Int J Biol Macromol. https://doi.org/10.1016/j.ijbiomac.2022.11.060

doi: 10.1016/j.ijbiomac.2022.11.060 pubmed: 36375666

Vanderweyde T, Apicco DJ, Youmans-Kidder K, Ash PEA, Cook C, Lummertz da Rocha E, Jansen-West K, Frame AA, Citro A, Leszyk JD et al (2016) Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity. Cell Rep 15(7):1455–1466. https://doi.org/10.1016/j.celrep.2016.04.045

doi: 10.1016/j.celrep.2016.04.045 pubmed: 27160897 pmcid: 5325702

Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U et al (2018) Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci 21(1):72–80. https://doi.org/10.1038/s41593-017-0022-z

doi: 10.1038/s41593-017-0022-z pubmed: 29273772

Rayman JB, Karl KA, Kandel ER (2018) TIA-1 self-multimerization, phase separation, and recruitment into stress granules are dynamically regulated by Zn(2). Cell Rep 22(1):59–71. https://doi.org/10.1016/j.celrep.2017.12.036

doi: 10.1016/j.celrep.2017.12.036 pubmed: 29298433

Mukherjee S, Panda D (2021) Contrasting effects of ferric and ferrous ions on oligomerization and droplet formation of tau: implications in tauopathies and neurodegeneration. ACS Chem Neurosci 12(23):4393–4405. https://doi.org/10.1021/acschemneuro.1c00377

doi: 10.1021/acschemneuro.1c00377 pubmed: 34783530

Sharma A, Pachauri V, Flora SJS (2018) Advances in multi-functional ligands and the need for metal-related pharmacology for the management of Alzheimer disease. Front Pharmacol 9:1247. https://doi.org/10.3389/fphar.2018.01247

doi: 10.3389/fphar.2018.01247 pubmed: 30498443 pmcid: 6249274

Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H, Mandelkow E (2009) Development of tau aggregation inhibitors for Alzheimer’s disease. Angew Chem Int Ed Engl 48(10):1740–1752. https://doi.org/10.1002/anie.200802621

doi: 10.1002/anie.200802621 pubmed: 19189357

Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C et al (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5(1):eaau3333. https://doi.org/10.1126/sciadv.aau3333

Himmelstein DS, Ward SM, Lancia JK, Patterson KR, Binder LI (2012) Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther 136(1):8–22. https://doi.org/10.1016/j.pharmthera.2012.07.001

doi: 10.1016/j.pharmthera.2012.07.001 pubmed: 22790092 pmcid: 3697479

Lo CH, Lim CK, Ding Z, Wickramasinghe SP, Braun AR, Ashe KH, Rhoades E, Thomas DD, Sachs JN (2019) Targeting the ensemble of heterogeneous tau oligomers in cells: a novel small molecule screening platform for tauopathies. Alzheimers Dement 15(11):1489–1502. https://doi.org/10.1016/j.jalz.2019.06.4954

doi: 10.1016/j.jalz.2019.06.4954 pubmed: 31653529 pmcid: 7038631

Rane JS, Bhaumik P, Panda D (2017) Curcumin inhibits tau aggregation and disintegrates preformed tau filaments in vitro. J Alzheimer’s Dis 60(3):999–1014. https://doi.org/10.3233/jad-170351

Jonchhe S, Pan W, Pokhrel P, Mao H (2022) Small molecules modulate liquid-to-solid transitions in phase-separated tau condensates. Angew Chem Int Ed Engl 61(23):e202113156. https://doi.org/10.1002/anie.202113156

doi: 10.1002/anie.202113156 pubmed: 35320624 pmcid: 9156559

Miyasaka T, Xie C, Yoshimura S, Shinzaki Y, Yoshina S, Kage-Nakadai E, Mitani S, Ihara Y (2016) Curcumin improves tau-induced neuronal dysfunction of nematodes. Neurobiol Aging 39:69–81. https://doi.org/10.1016/j.neurobiolaging.2015.11.004

doi: 10.1016/j.neurobiolaging.2015.11.004 pubmed: 26923403

Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P et al (2013) Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice. J Biol Chem 288(6):4056–4065. https://doi.org/10.1074/jbc.M112.393751

doi: 10.1074/jbc.M112.393751 pubmed: 23264626

Pradhan A, Mishra S, Surolia A, Panda D (2021) C1 inhibits liquid-liquid phase separation and oligomerization of tau and protects neuroblastoma cells against toxic tau oligomers. ACS Chem Neurosci 12(11):1989–2002. https://doi.org/10.1021/acschemneuro.1c00098

doi: 10.1021/acschemneuro.1c00098 pubmed: 34008959

Venkatramani A, Mukherjee S, Kumari A, Panda D (2022) Shikonin impedes phase separation and aggregation of tau and protects SH-SY5Y cells from the toxic effects of tau oligomers. Int J Biol Macromol 204:19–33. https://doi.org/10.1016/j.ijbiomac.2022.01.172

doi: 10.1016/j.ijbiomac.2022.01.172 pubmed: 35120943

Dai B, Zhong T, Chen ZX, Chen W, Zhang N, Liu XL, Wang LQ, Chen J, Liang Y (2021) Myricetin slows liquid-liquid phase separation of Tau and activates ATG5-dependent autophagy to suppress Tau toxicity. J Biol Chem 297(4):101222. https://doi.org/10.1016/j.jbc.2021.101222

doi: 10.1016/j.jbc.2021.101222 pubmed: 34560101 pmcid: 8551527

Ramesh M, Balachandra C, Baruah P, Govindaraju T (2022) Cyclic dipeptide-based small molecules modulate zinc-mediated liquid-liquid phase separation of tau. J Pept Sci:e3465. https://doi.org/10.1002/psc.3465

Lin Y, McCarty J, Rauch JN, Delaney KT, Kosik KS, Fredrickson GH, Shea JE, Han S (2019) Narrow equilibrium window for complex coacervation of tau and RNA under cellular conditions. eLife 8. https://doi.org/10.7554/eLife.42571

Boyko S, Qi X, Chen TH, Surewicz K, Surewicz WK (2019) Liquid-liquid phase separation of tau protein: the crucial role of electrostatic interactions. J Biol Chem 294(29):11054–11059. https://doi.org/10.1074/jbc.AC119.009198

doi: 10.1074/jbc.AC119.009198 pubmed: 31097543 pmcid: 6643045

Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F et al (2018) FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell 173(3):720–34.e15. https://doi.org/10.1016/j.cell.2018.03.056

doi: 10.1016/j.cell.2018.03.056 pubmed: 29677515 pmcid: 5927716

Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC, O’Donovan K, Fare CM, Diaz Z, Singh N et al (2018) Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173(3):677–92.e20. https://doi.org/10.1016/j.cell.2018.03.002

doi: 10.1016/j.cell.2018.03.002 pubmed: 29677512 pmcid: 5911940

Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp MD, Simons M, Niessing D, Madl T et al (2018) Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173(3):706–19.e13. https://doi.org/10.1016/j.cell.2018.03.004

doi: 10.1016/j.cell.2018.03.004 pubmed: 29677514

Ash PEA, Lei S, Shattuck J, Boudeau S, Carlomagno Y, Medalla M, Mashimo BL, Socorro G, Al-Mohanna LFA, Jiang L et al (2021) TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau. Proc Natl Acad Sci USA 118(9). https://doi.org/10.1073/pnas.2014188118

Aitken A (2006) 14–3-3 proteins: a historic overview. Semin Cancer Biol 16(3):162–172. https://doi.org/10.1016/j.semcancer.2006.03.005

doi: 10.1016/j.semcancer.2006.03.005 pubmed: 16678438

Hernández F, Cuadros R, Avila J (2004) Zeta 14–3-3 protein favours the formation of human tau fibrillar polymers. Neurosci Lett 357(2):143–146. https://doi.org/10.1016/j.neulet.2003.12.049

doi: 10.1016/j.neulet.2003.12.049 pubmed: 15036595

Han Y, Ye H, Li P, Zeng Y, Yang J, Gao M, Su Z, Huang Y (2022) In vitro characterization and molecular dynamics simulation reveal mechanism of 14–3-3ζ regulated phase separation of the tau protein. Int J Biol Macromol 208:1072–1081. https://doi.org/10.1016/j.ijbiomac.2022.03.215

doi: 10.1016/j.ijbiomac.2022.03.215 pubmed: 35381286

Chen J, Ma W, Yu J, Wang X, Qian H, Li P, Ye H, Han Y, Su Z, Gao M et al (2023) (-)-Epigallocatechin-3-gallate, a polyphenol from green tea, regulates the liquid-liquid phase separation of Alzheimer’s-related protein tau. J Agric Food Chem 71(4):1982–1993. https://doi.org/10.1021/acs.jafc.2c07799

doi: 10.1021/acs.jafc.2c07799 pubmed: 36688583

Ferrer-Acosta Y, Rodríguez-Cruz EN, Orange F, De Jesús-Cortés H, Madera B, Vaquer-Alicea J, Ballester J, Guinel MJ, Bloom GS, Vega IE (2013) EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer’s disease. J Neurochem 125(6):921–931. https://doi.org/10.1111/jnc.12155

doi: 10.1111/jnc.12155 pubmed: 23331044 pmcid: 3676478

Vega IE, Umstead A, Kanaan NM (2019) EFhd2 affects tau liquid-liquid phase separation. Front Neurosci 13:845. https://doi.org/10.3389/fnins.2019.00845

doi: 10.3389/fnins.2019.00845 pubmed: 31456657 pmcid: 6700279

Darling AL, Dahrendorff J, Creodore SG, Dickey CA, Blair LJ, Uversky VN (2021) Small heat shock protein 22 kDa can modulate the aggregation and liquid-liquid phase separation behavior of tau. Protein science : a publication of the Protein Society 30(7):1350–1359. https://doi.org/10.1002/pro.4060

Liu Z, Zhang S, Gu J, Tong Y, Li Y, Gui X, Long H, Wang C, Zhao C, Lu J et al (2020) Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation. Nat Struct Mol Biol 27(4):363–372. https://doi.org/10.1038/s41594-020-0399-3

doi: 10.1038/s41594-020-0399-3 pubmed: 32231288

Yu H, Lu S, Gasior K, Singh D, Vazquez-Sanchez S, Tapia O, Toprani D, Beccari MS, Yates JR, 3rd, Da Cruz S et al (2021) HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells. Science 371(6529). https://doi.org/10.1126/science.abb4309

Wang K, Liu JQ, Zhong T, Liu XL, Zeng Y, Qiao X, Xie T, Chen Y, Gao YY, Tang B et al (2020) Phase separation and cytotoxicity of tau are modulated by protein disulfide isomerase and S-nitrosylation of this molecular chaperone. J Mol Biol 432(7):2141–2163. https://doi.org/10.1016/j.jmb.2020.02.013

doi: 10.1016/j.jmb.2020.02.013 pubmed: 32087196

Babu M, Favretto F, Rankovic M, Zweckstetter M (2022) Peptidyl prolyl isomerase A modulates the liquid-liquid phase separation of proline-rich IDPs. J Am Chem Soc 144(35):16157–16163. https://doi.org/10.1021/jacs.2c07149

doi: 10.1021/jacs.2c07149 pubmed: 36018855 pmcid: 9460772

Moreira GG, Gomes CM (2023) Tau liquid-liquid phase separation is modulated by the Ca(2+) -switched chaperone activity of the S100B protein. J Neurochem. https://doi.org/10.1111/jnc.15756

doi: 10.1111/jnc.15756 pubmed: 37984072

Gerson JE, Sengupta U, Lasagna-Reeves CA, Guerrero-Muñoz MJ, Troncoso J, Kayed R (2014) Characterization of tau oligomeric seeds in progressive supranuclear palsy. Acta Neuropathol Commun 2:73. https://doi.org/10.1186/2051-5960-2-73

doi: 10.1186/2051-5960-2-73 pubmed: 24927818 pmcid: 4229782

Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17(1):5–21. https://doi.org/10.1038/nrn.2015.1

doi: 10.1038/nrn.2015.1 pubmed: 26631930

Guo JL, Lee VM (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20(2):130–138. https://doi.org/10.1038/nm.3457

doi: 10.1038/nm.3457 pubmed: 24504409 pmcid: 4011661

Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210. https://doi.org/10.1146/annurev-neuro-072116-031153

doi: 10.1146/annurev-neuro-072116-031153 pubmed: 28772101

Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4(1):49–60. https://doi.org/10.1038/nrn1007

doi: 10.1038/nrn1007 pubmed: 12511861

Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185. https://doi.org/10.1126/science.1566067

doi: 10.1126/science.1566067 pubmed: 1566067

Jakob-Roetne R, Jacobsen H (2009) Alzheimer’s disease: from pathology to therapeutic approaches. Angew Chem Int Ed Engl 48(17):3030–3059. https://doi.org/10.1002/anie.200802808

doi: 10.1002/anie.200802808 pubmed: 19330877

Lichtenthaler SF, Haass C, Steiner H (2011) Regulated intramembrane proteolysis–lessons from amyloid precursor protein processing. J Neurochem 117(5):779–796. https://doi.org/10.1111/j.1471-4159.2011.07248.x

doi: 10.1111/j.1471-4159.2011.07248.x pubmed: 21413990

Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112. https://doi.org/10.1038/nrm2101

doi: 10.1038/nrm2101 pubmed: 17245412

Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2(5):a006270. https://doi.org/10.1101/cshperspect.a006270

doi: 10.1101/cshperspect.a006270 pubmed: 22553493 pmcid: 3331683

Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3. https://doi.org/10.1186/1756-6606-4-3

doi: 10.1186/1756-6606-4-3 pubmed: 21214928 pmcid: 3022812

Jin C, Wang J, Wang Y, Jia B, Guo X, Yang G, Xu P, Greengard P, Zhou R, Shi Y (2022) Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation. Proc Natl Acad Sci USA 119(12):e2122292119. https://doi.org/10.1073/pnas.2122292119

doi: 10.1073/pnas.2122292119 pubmed: 35298330 pmcid: 8944281

Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li QX, Martins R, Rowe C et al (2018) High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554(7691):249–254. https://doi.org/10.1038/nature25456

doi: 10.1038/nature25456 pubmed: 29420472

Doecke JD, Pérez-Grijalba V, Fandos N, Fowler C, Villemagne VL, Masters CL, Pesini P, Sarasa M (2020) Total Aβ(42)/Aβ(40) ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis. Neurology 94(15):e1580–e1591. https://doi.org/10.1212/wnl.0000000000009240

doi: 10.1212/wnl.0000000000009240 pubmed: 32179698 pmcid: 7251518

Teunissen CE, Verberk IMW, Thijssen EH, Vermunt L, Hansson O, Zetterberg H, van der Flier WM, Mielke MM, Del Campo M (2022) Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol 21(1):66–77. https://doi.org/10.1016/s1474-4422(21)00361-6

doi: 10.1016/s1474-4422(21)00361-6 pubmed: 34838239

Connor JP, Quinn SD, Schaefer C (2022) Sticker-and-spacer model for amyloid beta condensation and fibrillation. Front Mol Neurosci 15:962526. https://doi.org/10.3389/fnmol.2022.962526

doi: 10.3389/fnmol.2022.962526 pubmed: 36311031 pmcid: 9611774

Chu X, Sun T, Li Q, Xu Y, Zhang Z, Lai L, Pei J (2022) Prediction of liquid-liquid phase separating proteins using machine learning. BMC Bioinformatics 23(1):72. https://doi.org/10.1186/s12859-022-04599-w

doi: 10.1186/s12859-022-04599-w pubmed: 35168563 pmcid: 8845408

Li Y, Gu J, Liu C, Li D (2022) A high-throughput method for exploring the parameter space of protein liquid-liquid phase separation. Cell Rep Phys Sci 3(3). https://doi.org/10.1016/j.xcrp.2022.100764

Gui X, Feng S, Li Z, Li Y, Reif B, Shi B, Niu Z (2023) Liquid-liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation. J Biol Chem 299(3):102926. https://doi.org/10.1016/j.jbc.2023.102926

doi: 10.1016/j.jbc.2023.102926 pubmed: 36682493 pmcid: 9974441

Kostylev MA, Tuttle MD, Lee S, Klein LE, Takahashi H, Cox TO, Gunther EC, Zilm KW, Strittmatter SM (2018) Liquid and hydrogel phases of PrP(C) linked to conformation shifts and triggered by Alzheimer’s amyloid-β oligomers. Mol Cell 72(3):426–43.e12. https://doi.org/10.1016/j.molcel.2018.10.009

doi: 10.1016/j.molcel.2018.10.009 pubmed: 30401430 pmcid: 6226277

Oskarsson ME, Paulsson JF, Schultz SW, Ingelsson M, Westermark P, Westermark GT (2015) In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease. Am J Pathol 185(3):834–846. https://doi.org/10.1016/j.ajpath.2014.11.016

doi: 10.1016/j.ajpath.2014.11.016 pubmed: 25700985

O’Nuallain B, Williams AD, Westermark P, Wetzel R (2004) Seeding specificity in amyloid growth induced by heterologous fibrils. J Biol Chem 279(17):17490–17499. https://doi.org/10.1074/jbc.M311300200

doi: 10.1074/jbc.M311300200 pubmed: 14752113

Pytowski L, Vaux DJ, Jean L (2021) The kinetics of islet amyloid polypeptide phase-separated system and hydrogel formation are critically influenced by macromolecular crowding. Biochem J 478(15):3025–3046. https://doi.org/10.1042/bcj20210384

doi: 10.1042/bcj20210384 pubmed: 34313292

Al-Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9(11):617–628. https://doi.org/10.1038/nrneurol.2013.203

doi: 10.1038/nrneurol.2013.203 pubmed: 24126629

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. https://doi.org/10.1126/science.1134108

doi: 10.1126/science.1134108 pubmed: 17023659

Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, Liesinger AM, Petersen RC, Parisi JE, Dickson DW (2016) Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 131(4):571–585. https://doi.org/10.1007/s00401-016-1537-1

doi: 10.1007/s00401-016-1537-1 pubmed: 26810071 pmcid: 5946692

Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF et al (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127(6):811–824. https://doi.org/10.1007/s00401-014-1269-z

doi: 10.1007/s00401-014-1269-z pubmed: 24659241 pmcid: 4172544

Babinchak WM, Haider R, Dumm BK, Sarkar P, Surewicz K, Choi JK, Surewicz WK (2019) The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain. J Biol Chem 294(16):6306–6317. https://doi.org/10.1074/jbc.RA118.007222

doi: 10.1074/jbc.RA118.007222 pubmed: 30814253 pmcid: 6484124

French RL, Grese ZR, Aligireddy H, Dhavale DD, Reeb AN, Kedia N, Kotzbauer PT, Bieschke J, Ayala YM (2019) Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation. J Biol Chem 294(17):6696–6709. https://doi.org/10.1074/jbc.RA118.005889

doi: 10.1074/jbc.RA118.005889 pubmed: 30824544 pmcid: 6497947

Sun Y, Medina Cruz A, Hadley KC, Galant NJ, Law R, Vernon RM, Morris VK, Robertson J, Chakrabartty A (2019) Physiologically important electrolytes as regulators of TDP-43 aggregation and droplet-phase behavior. Biochemistry 58(6):590–607. https://doi.org/10.1021/acs.biochem.8b00842

doi: 10.1021/acs.biochem.8b00842 pubmed: 30489059

McGurk L, Gomes E, Guo L, Shorter J, Bonini NM (2018) Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo-filamentous aggregation. Biochemistry 57(51):6923–6926. https://doi.org/10.1021/acs.biochem.8b00910

doi: 10.1021/acs.biochem.8b00910 pubmed: 30540446

Dang M, Kang J, Lim L, Li Y, Wang L, Song J (2020) ATP is a cryptic binder of TDP-43 RRM domains to enhance stability and inhibit ALS/AD-associated fibrillation. Biochem Biophys Res Commun 522(1):247–253. https://doi.org/10.1016/j.bbrc.2019.11.088

doi: 10.1016/j.bbrc.2019.11.088 pubmed: 31759630

Dhakal S, Wyant CE, George HE, Morgan SE, Rangachari V (2021) Prion-like C-terminal domain of TDP-43 and α-synuclein interact synergistically to generate neurotoxic hybrid fibrils. J Mol Biol 433(10):166953. https://doi.org/10.1016/j.jmb.2021.166953

doi: 10.1016/j.jmb.2021.166953 pubmed: 33771571 pmcid: 8085152

Irwin DJ, Lee VM, Trojanowski JQ (2013) Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci 14(9):626–636. https://doi.org/10.1038/nrn3549

doi: 10.1038/nrn3549 pubmed: 23900411 pmcid: 4017235

Siegert A, Rankovic M, Favretto F, Ukmar-Godec T, Strohäker T, Becker S, Zweckstetter M (2021) Interplay between tau and α-synuclein liquid-liquid phase separation. Protein science : a publication of the Protein Society 30(7):1326–1336. https://doi.org/10.1002/pro.4025

Giasson B, Forman M, Higuchi M, Golbe L, Graves C, Kotzbauer P, Trojanowski J, Lee V (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science (New York, NY) 300(5619):636–640. https://doi.org/10.1126/science.1082324

doi: 10.1126/science.1082324

Guo J, Covell D, Daniels J, Iba M, Stieber A, Zhang B, Riddle D, Kwong L, Xu Y, Trojanowski J et al (2013) Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154(1):103–117. https://doi.org/10.1016/j.cell.2013.05.057

doi: 10.1016/j.cell.2013.05.057 pubmed: 23827677

Gracia P, Polanco D, Tarancón-Díez J, Serra I, Bracci M, Oroz J, Laurents DV, García I, Cremades N (2022) Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau. Nat Commun 13(1):4586. https://doi.org/10.1038/s41467-022-32350-9

doi: 10.1038/s41467-022-32350-9 pubmed: 35933508 pmcid: 9357037

Aoki S, Liu AW, Zucca A, Zucca S, Wickens JR (2015) Role of striatal cholinergic interneurons in set-shifting in the rat. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(25):9424–9431. https://doi.org/10.1523/jneurosci.0490-15.2015

Nonaka T, Masuda-Suzukake M, Hasegawa M (2018) Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases. Neuropathology 38(1):64–71. https://doi.org/10.1111/neup.12427

Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ (2014) Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegener 9:43. https://doi.org/10.1186/1750-1326-9-43

doi: 10.1186/1750-1326-9-43 pubmed: 25352339 pmcid: 4230508

Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J, Soto C (2010) Molecular cross talk between misfolded proteins in animal models of Alzheimer’s and prion diseases. J Neurosci 30(13):4528–4535. https://doi.org/10.1523/jneurosci.5924-09.2010

Zumbro E, Alexander-Katz A (2021) Multivalent polymers can control phase boundary, dynamics, and organization of liquid-liquid phase separation. PLoS ONE 16(11):e0245405. https://doi.org/10.1371/journal.pone.0245405

doi: 10.1371/journal.pone.0245405 pubmed: 34748548 pmcid: 8575181

Ning W, Guo Y, Lin S, Mei B, Wu Y, Jiang P, Tan X, Zhang W, Chen G, Peng D et al (2020) DrLLPS: a data resource of liquid-liquid phase separation in eukaryotes. Nucleic Acids Res 48(D1):D288–D295. https://doi.org/10.1093/nar/gkz1027

doi: 10.1093/nar/gkz1027 pubmed: 31691822

Wang X, Zhou X, Yan Q, Liao S, Tang W, Xu P, Gao Y, Li Q, Dou Z, Yang W et al (2022) LLPSDB v2.0: an updated database of proteins undergoing liquid-liquid phase separation in vitro. Bioinformatics (Oxford, England) 38(7):2010–4. https://doi.org/10.1093/bioinformatics/btac026

Mészáros B, Erdős G, Szabó B, Schád É, Tantos Á, Abukhairan R, Horváth T, Murvai N, Kovács OP, Kovács M et al (2020) PhaSePro: the database of proteins driving liquid-liquid phase separation. Nucleic Acids Res 48(D1):D360–D367. https://doi.org/10.1093/nar/gkz848

doi: 10.1093/nar/gkz848 pubmed: 31612960

You K, Huang Q, Yu C, Shen B, Sevilla C, Shi M, Hermjakob H, Chen Y, Li T (2020) PhaSepDB: a database of liquid-liquid phase separation related proteins. Nucleic Acids Res 48(D1):D354–D359. https://doi.org/10.1093/nar/gkz847

doi: 10.1093/nar/gkz847 pubmed: 31584089

Youn JY, Dyakov BJA, Zhang J, Knight JDR, Vernon RM, Forman-Kay JD, Gingras AC (2019) Properties of stress granule and P-body proteomes. Mol Cell 76(2):286–294. https://doi.org/10.1016/j.molcel.2019.09.014

doi: 10.1016/j.molcel.2019.09.014 pubmed: 31626750

Zhu H, Fu H, Cui T, Ning L, Shao H, Guo Y, Ke Y, Zheng J, Lin H, Wu X et al (2022) RNAPhaSep: a resource of RNAs undergoing phase separation. Nucleic Acids Res 50:D340–D346. https://doi.org/10.1093/nar/gkab985

doi: 10.1093/nar/gkab985 pubmed: 34718740

Ishikawa-Ankerhold HC, Ankerhold R, Drummen GP (2012) Advanced fluorescence microscopy techniques–FRAP, FLIP, FLAP, FRET and FLIM. Molecules (Basel, Switzerland) 17(4):4047–4132. https://doi.org/10.3390/molecules17044047

doi: 10.3390/molecules17044047 pubmed: 22469598

Regy RM, Dignon GL, Zheng W, Kim YC, Mittal J (2020) Sequence dependent phase separation of protein-polynucleotide mixtures elucidated using molecular simulations. Nucleic Acids Res 48(22):12593–12603. https://doi.org/10.1093/nar/gkaa1099

doi: 10.1093/nar/gkaa1099 pubmed: 33264400 pmcid: 7736803

Bari KJ, Prakashchand DD (2021) Fundamental challenges and outlook in simulating liquid-liquid phase separation of intrinsically disordered proteins. J Phys Chem Lett 12(6):1644–1656. https://doi.org/10.1021/acs.jpclett.0c03404

Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP (2017) Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets. Cell 168(1–2):159–71.e14. https://doi.org/10.1016/j.cell.2016.11.054

doi: 10.1016/j.cell.2016.11.054 pubmed: 28041848

Bracha D, Walls MT, Wei MT, Zhu L, Kurian M, Avalos JL, Toettcher JE, Brangwynne CP (2018) Mapping local and global liquid phase behavior in living cells using photo-oligomerizable seeds. Cell 175(6):1467–80.e13. https://doi.org/10.1016/j.cell.2018.10.048

doi: 10.1016/j.cell.2018.10.048 pubmed: 30500534 pmcid: 6724719

Wang Z, Lou J, Zhang H (2022) Essence determines phenomenon: assaying the material properties of biological condensates. J Biol Chem 298(4):101782. https://doi.org/10.1016/j.jbc.2022.101782

doi: 10.1016/j.jbc.2022.101782 pubmed: 35245500 pmcid: 8958544

Nott TJ, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A, Craggs TD, Bazett-Jones DP, Pawson T, Forman-Kay JD et al (2015) Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell 57(5):936–947. https://doi.org/10.1016/j.molcel.2015.01.013

doi: 10.1016/j.molcel.2015.01.013 pubmed: 25747659 pmcid: 4352761

Wright PE, Dyson HJ (2015) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16(1):18–29. https://doi.org/10.1038/nrm3920

doi: 10.1038/nrm3920 pubmed: 25531225 pmcid: 4405151

Wille H, Drewes G, Biernat J, Mandelkow E, Mandelkow E (1992) Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol 118(3):573–584. https://doi.org/10.1083/jcb.118.3.573

doi: 10.1083/jcb.118.3.573 pubmed: 1639844

Lee G, Cowan N, Kirschner M (1988) The primary structure and heterogeneity of tau protein from mouse brain. Science 239(4837):285–288. https://doi.org/10.1126/science.3122323

doi: 10.1126/science.3122323 pubmed: 3122323

Majumdar A, Dogra P, Maity S, Mukhopadhyay S (2019) Liquid-liquid phase separation is driven by large-scale conformational unwinding and fluctuations of intrinsically disordered protein molecules. J Phys Chem Lett 10(14):3929–3936. https://doi.org/10.1021/acs.jpclett.9b01731

Babinchak WM, Surewicz WK (2020) Liquid-liquid phase separation and its mechanistic role in pathological protein aggregation. J Mol Biol 432(7):1910–1925. https://doi.org/10.1016/j.jmb.2020.03.004

doi: 10.1016/j.jmb.2020.03.004 pubmed: 32169484 pmcid: 7395662

Diner I, Hales CM, Bishof I, Rabenold L, Duong DM, Yi H, Laur O, Gearing M, Troncoso J, Thambisetty M et al (2014) Aggregation properties of the small nuclear ribonucleoprotein U1–70K in Alzheimer disease. J Biol Chem 289(51):35296–35313. https://doi.org/10.1074/jbc.M114.562959

doi: 10.1074/jbc.M114.562959 pubmed: 25355317 pmcid: 4271217

Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, Levey AI, Seyfried NT (2018) RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem 293(28):11047–11066. https://doi.org/10.1074/jbc.RA118.001747

doi: 10.1074/jbc.RA118.001747 pubmed: 29802200 pmcid: 6052236

Xue S, Gong R, He F, Li Y, Wang Y, Tan T, Luo SZ (2019) Low-complexity domain of U1–70K modulates phase separation and aggregation through distinctive basic-acidic motifs. Sci Adv 5(11):eaax5349. https://doi.org/10.1126/sciadv.aax5349

Liquid-liquid phase separation in Alzheimer's disease.

Journal

Informations de publication

Résumé

Identifiants

Types de publication

Langues

Sous-ensembles de citation

Subventions

Informations de copyright

Références

Auteurs

Qinggang Fu (Q)

Bixiang Zhang (B)

Xiaoping Chen (X)

Liang Chu (L)

Classifications MeSH