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Comment
. 2019 Apr 17;102(2):265-267.
doi: 10.1016/j.neuron.2019.03.041.

The Evolution of Phase-Separated TDP-43 in Stress

Benjamin Wolozin  1
Affiliations
Comment

The Evolution of Phase-Separated TDP-43 in Stress

Benjamin Wolozin. Neuron. .

Abstract

In this issue of Neuron, Gasset-Rosa et al. (2019) and Mann et al. (2019) demonstrate that cytoplasmic inclusions containing aggregated phosphorylated TDP-43 can evolve through three pathways: direct aggregation or phase-separated intermediates involving ejection from stress granules or seeding with exogenous fibrils. Interestingly, seeding with exogenous fibrils also induces cytoplasmic aggregates of nuclear pore proteins.

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Figures

Figure 1:
Figure 1:
Paths to formation of pathological TDP-43 granules. A) Basal conditions with TDP-43 in the nucleus. B) Stress or pathological seeds induce formation of cytoplasmic TDP-43 granules, as well as some TDP-43 not associated with RNA or stress granules. C) The TDP-43 matures into pathological TDP-43 granules. D) Neuropathology accrues as unresolvable components accumulate.
See this image and copyright information in PMC

Comment on

References

    1. Afroz T, Hock EM, Ernst P, Foglieni C, Jambeau M, Gilhespy LAB, Laferriere F, Maniecka Z, Pluckthun A, Mittl P, et al. (2017). Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat Commun 8, 45. - PMC - PubMed
    1. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, et al. (2017). Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371. - PMC - PubMed
    1. Gasset-Rosa F, Lu S, Yu H, Chen C, Melamed Z, Guo L, Shorter J, Da Cruz S, and Cleveland DW (2019). Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death. Neuron. - PMC - PubMed
    1. Jiang L, Ash PEA, Maziuk BF, Ballance HI, Boudeau S, Abdullatif AA, Orlando M, Petrucelli L, Ikezu T, and Wolozin B (2018). TIA1 regulates the generation and response to toxic tau oligomers. Acta Neuropathol - PMC - PubMed
    1. Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, Copley KE, Hurtle B, Portz B, Pyles NJ, et al. (2019). RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. - PMC - PubMed