TY  - JOUR
AU  - Uechi, Hiroyuki
AU  - Sridharan, Sindhuja
AU  - Nijssen, Jik
AU  - Bilstein, Jessica
AU  - Iglesias-Artola, Juan M
AU  - Kishigami, Satoshi
AU  - Casablancas-Antras, Virginia
AU  - Poser, Ina
AU  - Martinez, Eduardo J
AU  - Boczek, Edgar
AU  - Wagner, Michael
AU  - Tomschke, Nadine
AU  - de Jesus Domingues, António M
AU  - Pal, Arun
AU  - Doeleman, Thom
AU  - Kour, Sukhleen
AU  - Anderson, Eric Nathaniel
AU  - Stein, Frank
AU  - Lee, Hyun O
AU  - Zhang, Xiaojie
AU  - Fritsch, Anatol W
AU  - Jahnel, Marcus
AU  - Fürsch, Julius
AU  - Murthy, Anastasia C
AU  - Alberti, Simon
AU  - Bickle, Marc
AU  - Fawzi, Nicolas L
AU  - Nadler, André
AU  - David, Della C
AU  - Pandey, Udai B
AU  - Hermann, Andreas
AU  - Stengel, Florian
AU  - Davis, Benjamin G
AU  - Baldwin, Andrew J
AU  - Savitski, Mikhail M
AU  - Hyman, Anthony A
AU  - Wheeler, Richard J
TI  - Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
JO  - Nature chemical biology
VL  - 21
IS  - 10
SN  - 1552-4450
CY  - Basingstoke
PB  - Nature Publishing Group
M1  - DZNE-2025-01123
SP  - 1577 - 1588
PY  - 2025
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Oxidation-Reduction: drug effects
KW  - Humans
KW  - Animals
KW  - Stress Granules: metabolism
KW  - Stress Granules: drug effects
KW  - Small Molecule Libraries: pharmacology
KW  - Small Molecule Libraries: chemistry
KW  - Mice
KW  - Disease Models, Animal
KW  - Small Molecule Libraries (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40369342
C2  - pmc:PMC12463676
DO  - DOI:10.1038/s41589-025-01893-5
UR  - https://pub.dzne.de/record/281502
ER  -