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@ARTICLE{Uechi:281502,
author = {Uechi, Hiroyuki and Sridharan, Sindhuja and Nijssen, Jik
and Bilstein, Jessica and Iglesias-Artola, Juan M and
Kishigami, Satoshi and Casablancas-Antras, Virginia and
Poser, Ina and Martinez, Eduardo J and Boczek, Edgar and
Wagner, Michael and Tomschke, Nadine and de Jesus Domingues,
António M and Pal, Arun and Doeleman, Thom and Kour,
Sukhleen and Anderson, Eric Nathaniel and Stein, Frank and
Lee, Hyun O and Zhang, Xiaojie and Fritsch, Anatol W and
Jahnel, Marcus and Fürsch, Julius and Murthy, Anastasia C
and Alberti, Simon and Bickle, Marc and Fawzi, Nicolas L and
Nadler, André and David, Della C and Pandey, Udai B and
Hermann, Andreas and Stengel, Florian and Davis, Benjamin G
and Baldwin, Andrew J and Savitski, Mikhail M and Hyman,
Anthony A and Wheeler, Richard J},
title = {{S}mall-molecule dissolution of stress granules by redox
modulation benefits {ALS} models.},
journal = {Nature chemical biology},
volume = {21},
number = {10},
issn = {1552-4450},
address = {Basingstoke},
publisher = {Nature Publishing Group},
reportid = {DZNE-2025-01123},
pages = {1577 - 1588},
year = {2025},
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.},
keywords = {Amyotrophic Lateral Sclerosis: metabolism / Amyotrophic
Lateral Sclerosis: drug therapy / Amyotrophic Lateral
Sclerosis: genetics / Amyotrophic Lateral Sclerosis:
pathology / Oxidation-Reduction: drug effects / Humans /
Animals / Stress Granules: metabolism / Stress Granules:
drug effects / Small Molecule Libraries: pharmacology /
Small Molecule Libraries: chemistry / Mice / Disease Models,
Animal / Small Molecule Libraries (NLM Chemicals)},
cin = {AG Hermann / AG David},
ddc = {570},
cid = {I:(DE-2719)1511100 / I:(DE-2719)1210004},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 899 -
ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40369342},
pmc = {pmc:PMC12463676},
doi = {10.1038/s41589-025-01893-5},
url = {https://pub.dzne.de/record/281502},
}