Journal Article

DZNE-2025-01123

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Small-molecule dissolution of stress granules by redox modulation benefits ALS models.

Uechi, H. ; Sridharan, S. ; Nijssen, J. ; Bilstein, J. ; Iglesias-Artola, J. M. ; Kishigami, S. ; Casablancas-Antras, V. ; Poser, I. ; Martinez, E. J. ; Boczek, E. ; Wagner, M. ; Tomschke, N. ; de Jesus Domingues, A. M. ; Pal, A. ; Doeleman, T. ; Kour, S. ; Anderson, E. N. ; Stein, F. ; Lee, H. O. ; Zhang, X. ; Fritsch, A. W. ; Jahnel, M. ; Fürsch, J. ; Murthy, A. C. ; Alberti, S. ; Bickle, M. ; Fawzi, N. L. ; Nadler, A. ; David, D. C.DZNE* ; Pandey, U. B. ; Hermann, A.DZNE* ; Stengel, F. ; Davis, B. G. ; Baldwin, A. J. ; Savitski, M. M. ; Hyman, A. A. ; Wheeler, R. J.

2025
Nature Publishing Group Basingstoke

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Please use a persistent id in citations: doi:10.1038/s41589-025-01893-5

Abstract: Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.

Keyword(s): Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: drug therapy (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Oxidation-Reduction: drug effects (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Stress Granules: metabolism (MeSH) ; Stress Granules: drug effects (MeSH) ; Small Molecule Libraries: pharmacology (MeSH) ; Small Molecule Libraries: chemistry (MeSH) ; Mice (MeSH) ; Disease Models, Animal (MeSH) ; Small Molecule Libraries

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)
2. Protein Aggregation and Aging (AG David)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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