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

Samuel J. Resnick, Seema Qamar, Pushya Krishna, Vladislav Korobeynikov, Hannes Ausserwoger, Alyssa Miller, Pietro Esposito, Juan A. Varela, Jenny Sheng, Lei Haley Huang, Jonathon Nixon-Abell, Schuyler Melore, Chyi Wei Chung, Nino F. Läubli, Sofia Kapsiani, Xuecong Li, Jingshu Wang, Nancy Zhang, Mahabub Maraj Alam, Alondra S. Burguete, Theresa C. Swayne, Yanyan Chen, Ya-Cheng Liao, Neil A. Shneider, Michele Vendruscolo, Tuomas P. J. Knowles, Clemens F. Kaminski, Francesco Simone Ruggeri, Gabriele S. Kaminski Schierle, Peter St George-Hyslop () and Alejandro Chavez ()
Additional contact information
Samuel J. Resnick: Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Seema Qamar: University of Cambridge, Cambridge Institute for Medical Research, Department of Clinical Neurosciences
Pushya Krishna: University of California San Diego, Department of Pediatrics
Vladislav Korobeynikov: Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Hannes Ausserwoger: Lensfield Road, Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge
Alyssa Miller: Lensfield Road, Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge
Pietro Esposito: University of St Andrews, School of Biology
Juan A. Varela: University of St Andrews, School of Physics and Astronomy
Jenny Sheng: Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Lei Haley Huang: Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Jonathon Nixon-Abell: University of Cambridge, Cambridge Institute for Medical Research, Department of Clinical Neurosciences
Schuyler Melore: Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Chyi Wei Chung: Philippa Fawcett Drive, Department of Chemical Engineering and Biotechnology, University of Cambridge
Nino F. Läubli: Philippa Fawcett Drive, Department of Chemical Engineering and Biotechnology, University of Cambridge
Sofia Kapsiani: Philippa Fawcett Drive, Department of Chemical Engineering and Biotechnology, University of Cambridge
Xuecong Li: Wageningen University & Research, Laboratory of Organic Chemistry, Stippeneng 4, 6703 WE
Jingshu Wang: The University of Chicago, Department of Statistics
Nancy Zhang: University of Pennsylvania, Department of Statistics
Mahabub Maraj Alam: Columbia University Irving Medical Center, Center for Motor Neuron Biology and Disease
Alondra S. Burguete: Columbia University Irving Medical Center, Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain
Theresa C. Swayne: Columbia University Irving Medical Center; Columbia University Irving Medical Center, Department of Pathology and Cell Biology
Yanyan Chen: Columbia University Irving Medical Center, Confocal and Specialized Microscopy Shared Resource in the Herbert Irving Comprehensive Cancer Center
Ya-Cheng Liao: Columbia University Medical Center, Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain
Neil A. Shneider: Columbia University Irving Medical Center, Center for Motor Neuron Biology and Disease
Michele Vendruscolo: Lensfield Road, Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge
Tuomas P. J. Knowles: Lensfield Road, Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge
Clemens F. Kaminski: Philippa Fawcett Drive, Department of Chemical Engineering and Biotechnology, University of Cambridge
Francesco Simone Ruggeri: Wageningen University & Research, Laboratory of Organic Chemistry, Stippeneng 4, 6703 WE
Gabriele S. Kaminski Schierle: Philippa Fawcett Drive, Department of Chemical Engineering and Biotechnology, University of Cambridge
Peter St George-Hyslop: Lensfield Road, Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge
Alejandro Chavez: University of California San Diego, Department of Pediatrics

Nature Communications, 2025, vol. 16, issue 1, 1-27

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65178-0

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