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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Samuel J. Resnick,
  • Seema Qamar,
  • Pushya Krishna,
  • Vlad A. Korben,
  • 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,
  • Alejandro Chavez

摘要

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.