Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization

Gkekas, I.; Pliatsika, K.; Mylonas, S.; Katsamakas, S.; Axenopoulos, A.; Kostova, S.; Wanker, E. E.; Hadjipavlou-Litina, D.; Xanthopoulos, K.; Daras, P.; Petrakis, S.

doi:10.1101/2025.03.17.643445

bioRxiv · 10.1101/2025.03.17.643445

Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization

Gkekas, I.·Pliatsika, K.·Mylonas, S.·Katsamakas, S.·Axenopoulos, A.·Kostova, S.·Wanker, E. E.·Hadjipavlou-Litina, D.·Xanthopoulos, K.·Daras, P.·Petrakis, S.

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 that significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structure of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99-163 of ATXN1 and aa548-665 of MED15 are critical for this protein-protein interaction (PPI). We also show that the aa99-163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99-163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1.

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Gkekas, I., Pliatsika, K., Mylonas, S., Katsamakas, S., Axenopoulos, A., Kostova, S., Wanker, E. E., Hadjipavlou-Litina, D., Xanthopoulos, K., Daras, P., Petrakis, S.. 2025-03-17. Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization. https://doi.org/10.1101/2025.03.17.643445

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