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

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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Publication Details

Journal
Nature Communications
Published
2025-11-21
DOI
https://doi.org/10.1038/s41467-025-65178-0
Citations
1
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
1.39

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article

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

Juan A. Varela, Priti Krishna, Clemens F. Kaminski, Nancy R. Zhang et al.
1 citations
Nature Communications
Amyotrophic Lateral Sclerosis Research
1.39
article

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

Juan A. Varela, Priti Krishna, Clemens F. Kaminski, Nancy R. Zhang, Francesco Simone Ruggeri, Alejandro Chavez, Michele Vendruscolo, Tuomas P. J. Knowles, Lei Huang, Ya-Cheng Liao, Seema Qamar, Nino F. Läubli, Gabriele S. Kaminski Schierle, Chyi Wei Chung, Mahabub Alam, Peter St George‐Hyslop, Schuyler Melore, Xuecong Li, Vladislav A. Korobeynikov, Neil A. Shneider, Alondra Schweizer Burguete, Jingshu Wang, Samuel J. Resnick, Hannes Ausserwӧger, Sofia Kapsiani, Jonathon Nixon‐Abell, Pietro Esposito, Theresa C. Swayne, Yanyan Chen, Alyssa Miller, Jenny Sheng
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
University Health Network (CA), University of St Andrews (GB), University of Cambridge (GB), Columbia University Irving Medical Center (US), UC San Diego Health System (US), University of California San Diego (US), University of Chicago (US), Columbia University (US), University of Pennsylvania (US), Wageningen University & Research (NL)
National Science Foundation, Wellcome Trust, UK Research and Innovation, Consortium canadien en neurodégénérescence associée au vieillissement, Alzheimer's Society, Alzheimer Society, European Commission, Cambridge Trust, Novo Nordisk, National Institutes of Health, Irving Medical Center, Columbia University, Canadian Institutes of Health Research, Medical Research Council, National Cancer Institute
Openalex Percentile: Top 14%
Amyotrophic Lateral Sclerosis Research
1.39
DOIOpen Access PDFOpenAlex
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