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CFTR acts as a potential therapeutic target for attention deficit-hyperactivity disorder

ABSTRACT: The occurrence of attention deficit-hyperactivity disorder (ADHD) symptoms in patients with cystic fibrosis (CF) is substantially higher than in the general population, and the cystic fibrosis transmembrane conductance regulator (CFTR) is the pathogenic gene of cystic fibrosis, suggesting the potentially critical role of CFTR in ADHD. Here, we identified three heterozygous missense mutations (p.E217G, p.F316L and p.T1220I) in CFTR, segregating with ADHD in two consanguineous families with 6 affected individuals. Using the zebrafish model, we found that the cftr knockout line displays hyperactive, impulsive-like, and attention deficit-like behaviors, reminiscent of human ADHD patients. Single-cell RNA-seq of 7 dpf larvae identified clusters of neuron cells that were sensitive to cftr, especially, the number of dopaminergic neuron cells decreased in the cftr mutant fish. Bulk RNA-seq and proteomic analysis at the early gastrulation period showed that the expression of nerve system genes was abnormal. Notably, we tried to use CFTR activitors Lumacaftor (VX-809) and Ivacaftor (VX-770) to treat the ADHD zebrafish model (established by per1b mutant), and found enhanced CFTR activity could rescue the ADHD-like behaviors. In brief, we uncover the role of CFTR in ADHD pathogenesis and explore novel diagnoses and therapy for ADHD by targeting CFTR.

ORGANISM(S): Danio rerio

PROVIDER: GSE284214 | GEO | 2024/12/16

REPOSITORIES: GEO

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Project description:Cystic Fibrosis (CF) is a genetic disorder CF is caused by mutations of the gene encoding for the cystic fibrosis transmembrane conductance regulator protein (CFTR), a transmembrane anion channel expressed at the apical membrane of several organs, including the epithelial cells of the airway. CFTR mutations result in dysfunctional ion transport across the apical membrane at the surface of the epithelia, generating thickened and dehydrated secretions. In the lung, this leads to a decrease in the mucociliary clearance, favoring bacterial colonization and progressive obstruction of the duct. Although over 2000 CFTR variants have been identified so far, the most common mutation is a deletion of the phenylalanine in position 508 (F508del), which shows an allelic frequency of around 90% among CF patients. F508del-CFTR is incorrectly folded, causing its retention at the endoplasmic reticulum (ER) and subsequent proteasomal degradation. Among the several drugs available in CF pharmacological treatment, VX-809 (commercial name Lumacaftor) is the most used drug for patients carrying F508del-CFTR mutation. This drug corrects the aberrant folding of F508del-CFTR by favoring the correct intramolecular interactions, thus enabling a higher number of copies of the defective protein to reach the plasma membrane. Localization of Organelle Proteins by Isotope Tagging after Differential ultra-Centrifugation (LOPIT-DC, https://doi.org/10.1038/s41467-018-08191-w) workflow was used to study the spatial localization of proteins in the CFBE41o- cells and how it is impacted by CFTR rescue triggered by VX-809. LOPIT-DC is a powerful and well-established tool for the investigation of the spatial distribution of global proteome within cells, which combines subcellular fractionation based on differential centrifugation, quantitative mass spectrometry, and machine learning. Its application provides a global snapshot of the steady-state subcelluler distribution of proteins. The aim of this project is to identify proteins that change their cellular localization in association with the treatment, to uncover molecules that play a role in the trafficking of the defective CFTR to the plasma membrane.

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CFTR acts as a potential therapeutic target for attention deficit-hyperactivity disorder

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