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PHASE SEPARATION

Finding a chaperone for TDP-43

Nature Cell Biology volume 24, pages 1328–1330 (2022)Cite this article

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Aggregation of the RNA-binding protein TDP-43 is commonly observed in neurodegenerative disorders. A new study reveals that this process may be blocked by HSPB1, a small heat shock protein that can also regulate TDP-43 phase separation. This may be relevant to neurodegeneration, as loss of HSPB1 correlates with TDP-43 pathology.

Biomolecular condensation is mediated by phase separation, or liquid–liquid phase separation (LLPS), which consists of the de-mixing of biological macromolecules such as proteins and nucleic acids into dense and light phases. Mounting evidence suggests that biomolecular condensation has a central role in numerous cellular functions and mechanisms of disease, including cancer and neurodegeneration. RNA-binding proteins (RBPs) are characteristically prone to phase separation, and their function is modulated by LLPS1. Disruptions in the material properties of RBP condensates may generate irreversible aggregates linked to neurodegeneration2. The self-assembly of the RBP TDP-43 (TAR DNA-binding protein) in the cytoplasm has come under special scrutiny because TDP-43 aggregates in this compartment, and the corresponding nuclear depletion of the protein, are common features of various neurodegenerative disorders3. In particular, neuronal and glial TDP-43 inclusions are found in nearly all individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with ubiquitin-positive inclusions (FTLD-U)3. This pathology also accumulates in all cases of an Alzheimer’s-disease-associated dementia affecting the oldest population, known as limbic-predominant age-related TDP-43 encephalopathy (LATE)4. Therefore, understanding the biogenesis of TDP-43 aggregates and how their assembly may be controlled is of major therapeutic interest. In the current issue of Nature Cell Biology, Lu et al.5 characterize TDP-43 condensates formed in the cytoplasm under proteotoxic conditions and identify factors that may act as chaperones by inhibiting protein aggregation.

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Fig. 1: HSPB1 recruitment to TDP-43 condensates maintains dynamic properties under proteotoxic stress.

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Authors and Affiliations

  1. Edward Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA

    Yuna M. Ayala & Zachary R. Grese

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  1. Yuna M. Ayala
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  2. Zachary R. Grese
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Correspondence to Yuna M. Ayala.

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The authors declare no competing interests.

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Ayala, Y.M., Grese, Z.R. Finding a chaperone for TDP-43. Nat Cell Biol 24, 1328–1330 (2022). https://doi.org/10.1038/s41556-022-00987-9

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