Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders
Poch, D.; Mukherjee, C.; Mallik, S.; Todorow, V.; Kuiper, E. F. E. J.; Dhingra, N.; Surovtseva, Y. V.; Schlieker, C.
Show abstract
Aberrant biomolecular condensates are implicated in neurological disorders including ALS, frontotemporal dementia, and DYT1 dystonia, yet approaches to systematically identify their modulators remain limited. Here we establish MLF2 as a versatile condensate biomarker and develop CondenScreen, an integrated high-content screening and bioinformatic pipeline enabling identification of condensate modulators across chemical and genetic space. Screening 1,760 FDA-approved compounds in a cellular DYT1 dystonia model, we identify drugs that alter aberrant condensate properties, validating the platform for condensate-targeted drug discovery. In parallel, a genome-wide CRISPR/Cas9 screen links condensate accumulation to microcephaly genes and more than 10 additional neurodevelopmental disorders. Machine learning and confocal imaging resolves distinct condensate phenotypes: loss of microcephaly-associated ZNF335 results in nucleoplasmic condensates, whereas RNF26 deletion produces nuclear envelope condensates that phenocopy hallmarks of torsin deficiency. Our study provides a scalable resource for identifying corrective modulators of condensates and establishes a link between nuclear condensate accumulation and neurodevelopmental disorders.
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