TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.
Peter E.A. Ash,Shuwen Lei,Jenifer Shattuck,Samantha Boudeau,Yari Carlomagno,Maria Medalla,Bryce L Mashimo,Guillermo Socorro,Louloua F A Al-Mohanna,Lulu Jiang,Muhammet M Öztürk,Mark Knobel,Pavel Ivanov,Leonard Petrucelli,Susanne Wegmann,Nicholas M. Kanaan,Benjamin Wolozin +16 more
TLDR
In this paper, the interaction of tau with RNA and the RNA binding protein TIA1 is shown to drive phase separation at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG).Abstract:
Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.read more
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ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.
Kathryn R. Bowles,M. Catarina Silva,Kristen Whitney,Taylor B. Bertucci,Joshua E. Berlind,Jesse D. Lai,Jesse D. Lai,Jacob C. Garza,Nathan C. Boles,Sidhartha Mahali,Kevin H. Strang,Jacob A. Marsh,Cynthia Chen,Derian A. Pugh,Yiyuan Liu,Ronald E. Gordon,Susan K. Goderie,Rebecca Chowdhury,Steven Lotz,Keith P. Lane,John F. Crary,Stephen J. Haggarty,Celeste M. Karch,Justin K. Ichida,Alison Goate,Sally Temple +25 more
TL;DR: In this article, the authors used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration.
Journal ArticleDOI
Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy
Lulu Jiang,Weiwei Lin,Cheng Zhang,Peter E.A. Ash,Mamta Verma,Julian Kwan,Emily van Vliet,Zhuo Yang,Anna Lourdes Cruz,Samantha Boudeau,Brandon F. Maziuk,Shuwen Lei,Jaehyup Song,Victor E. Alvarez,Stacy Hovde,Jose F. Abisambra,Min Hao Kuo,Nicholas M. Kanaan,Melissa E. Murray,John F. Crary,Jian Zhao,Ji-Xin Cheng,Leonard Petrucelli,Hu Li,Andrew Emili,Benjamin Wolozin +25 more
TL;DR: In this paper, the authors used Cry2-based optogenetics to induce tau oligomers (oTau-c), which elicits tau phosphorylation, aggregation, and reduced protein synthesis.
Journal ArticleDOI
Tau liquid-liquid phase separation in neurodegenerative diseases.
TL;DR: Tau alone or in the presence of RNA has a high propensity to undergo liquid-liquid phase separation (LLPS), forming liquid droplets as mentioned in this paper , which may contribute to normal biological functions of the protein as well as to tau pathology in neurodegenerative diseases.
Journal ArticleDOI
Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates
Janine Hochmair,Christian Exner,Maximilian Franck,Alvaro Dominguez-Baquero,Lisa Diez,Hévila Brognaro,Matthew L. Kraushar,Thorsten Mielke,Helena Radbruch,Senthilvelrajan Kaniyappan,Sven Falke,Eckhard Mandelkow,Christian Betzel,Susanne Wegmann +13 more
TL;DR: It is found that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces.
Journal ArticleDOI
Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease.
Pamela J. McMillan,Pamela J. McMillan,Timothy J. Strovas,Misa Baum,Brooke K. Mitchell,Randall J. Eck,Nzinga Hendricks,Jeanna M. Wheeler,Caitlin S. Latimer,C. Dirk Keene,Brian C. Kraemer +10 more
TL;DR: In this paper, the authors used human pathological tissue and transgenic mice to identify Alzheimer's disease-specific cellular changes related to nuclear speckles, and they observed that the scaffold protein SRRM2 is mislocalized and accumulates in cytoplasmic lesions in AD brain tissue.
References
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Journal ArticleDOI
TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
Ian R. A. Mackenzie,Alexandra M. Nicholson,Mohona Sarkar,James Messing,Maria D. Purice,Cyril Pottier,Kavya Annu,Matt Baker,Ralph B. Perkerson,Aishe Kurti,Billie J. Matchett,Tanja Mittag,Jamshid Temirov,Ging-Yuek Robin Hsiung,Charles Krieger,Charles Krieger,Melissa E. Murray,Masato Kato,John D. Fryer,Leonard Petrucelli,Lorne Zinman,Sandra Weintraub,M.-Marsel Mesulam,Julia Keith,Sasha Zivkovic,Veronica Hirsch-Reinshagen,Raymond P. Roos,Stephan Züchner,Neill R. Graff-Radford,Ronald C. Petersen,Richard J. Caselli,Zbigniew K. Wszolek,Elizabeth Finger,Carol F. Lippa,Carol F. Lippa,David Lacomis,Heather Stewart,Dennis W. Dickson,Hong Joo Kim,Ekaterina Rogaeva,Eileen H. Bigio,Kevin B. Boylan,J. Paul Taylor,Rosa Rademakers +43 more
TL;DR: The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS-FTD pathogenesis.