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Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.

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Affiliations

  • 1. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
      Authors
    • Resnick SJ 1
    • Korobeynikov V 1, 11
    • Sheng J 1
    • Huang LH 1
    • Melore S 1
    (5 authors)
  • 2. Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
      Authors
    • Qamar S 2, 4
    • Nixon-Abell J 2
    (2 authors)
  • 3. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
      Authors
    • Krishna P 3
    • Chavez A 3
    (2 authors)
  • 4. Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Lensfield Road, Cambridge, UK.
      Authors
    • Qamar S 2, 4
    • Ausserwoger H 4
    • Miller A 4
    • Vendruscolo M 4
    • Knowles TPJ 4
    • St George-Hyslop P 4, 12
    (6 authors)
  • 5. School of Biology, University of St Andrews, St Andrews, UK.
      Authors
    • Esposito P 5
    (1 author)
    • Show all (15)

ORCIDs linked to this article

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Nature Communications, 21 Nov 2025, 16(1):10285
https://doi.org/10.1038/s41467-025-65178-0 PMID: 41271702 PMCID: PMC12638947

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Abstract 

Neurodegenerative disorders (NDDs) are a family of diseases that remain poorly treated despite their growing global health burden. To gain insight into the mechanisms and modulators of neurodegeneration, we developed a yeast-based multiplex genetic screening platform. Using this platform, 32 NDD-associated proteins are probed against a library of 132 molecular chaperones from both yeast and humans, and an unbiased set of ~900 human proteins. We identify both broadly active and specific modifiers of our various cellular models. To illustrate the translatability of this platform, we extensively characterize a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 modifies the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs). Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 revealed key residues required for its activity and identified variants with enhanced activity. Finally, we show that overexpression of DNAJB6 prevents motor neuron loss and the associated microglia activation in a mouse model of FUS-ALS.

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    Funding 

    Funders who supported this work.

    Alzheimer's Association (1)

    • Grant ID: ZEN-18-529769

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    Alzheimer's Society (2)

    • Grant ID: 016

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    • Grant ID: AS-PhD-19a-016

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    Amyotrophic Lateral Sclerosis Association (ALS Association) (1)

    • Grant ID: 21-IIA-571

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    Burroughs Wellcome Fund (BWF) (1)

    • Grant ID: Career Awards for Medical Scientists

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    European Research Council (3)

    • Grant ID: 804581

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    • Grant ID: 10100161

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    • Grant ID: 337969

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    Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) (1)

    • Grant ID: 406915, Canadian Consortium on Neurodegeneration in Aging Grant

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    Medical Research Council (1)

    • Grant ID: MR/K02292X/1

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    NCI NIH HHS (1)

    • Grant ID: P30 CA013696

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    NHGRI NIH HHS (1)

    • Grant ID: R01 HG006137

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    NINDS NIH HHS (2)

    • Grant ID: F31 NS111851

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    • Grant ID: R01 NS106236

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    National Science Foundation (NSF) (1)

    • Grant ID: 2113646

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    U.S. Department of Defense (United States Department of Defense) (1)

    • Grant ID: AL190073

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    U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (1)

    • Grant ID: 5R01NS106236

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    U.S. Department of Health & Human Services | National Institutes of Health (NIH) (2)

    • Grant ID: F31NS111851

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    • Grant ID: 2R01HG006137-10

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    Wellcome Trust (2)

    • Grant ID: 065807/Z/01/Z

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    • Grant ID: 203249/Z/16/Z

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