Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency

Gregor A, Distel L, Ekici AB, Kirchner P, Uebe S, Krumbiegel M, Turan S, Winner B, Zweier C (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Human Genetics and Genomics Advances Cell Press

Book Volume: 6

Article Number: 100425

Journal Issue: 2

DOI: 10.1016/j.xhgg.2025.100425

Abstract

Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous system-related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR-Cas9 and a Drosophila model using tissue-specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration, and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome-activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.

Authors with CRIS profile

Arif Bülent Ekici Institute of Human Genetics Steffen Uebe Institute of Human Genetics Mandy Krumbiegel Institute of Human Genetics Sören Turan Friedrich-Alexander-Universität Erlangen-Nürnberg Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Inselspital, Universitätsspital Bern CH Switzerland (CH)

How to cite

APA:

Gregor, A., Distel, L., Ekici, A.B., Kirchner, P., Uebe, S., Krumbiegel, M.,... Zweier, C. (2025). Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency. Human Genetics and Genomics Advances, 6(2). https://doi.org/10.1016/j.xhgg.2025.100425

MLA:

Gregor, Anne, et al. "Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency." Human Genetics and Genomics Advances 6.2 (2025).

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