Assessing Drug Administration Techniques in Zebrafish Models of Neurological Disease.

Neurological diseases, including neurodegenerative and neurodevelopmental disorders, affect nearly one in six of the world's population. The burden of the resulting deaths and disability is set to rise during the next few decades as a consequence of an aging population. To address this, zebrafish have become increasingly prominent as a model for studying human neurological diseases and exploring potential therapies. Zebrafish offer numerous benefits, such as genetic homology and brain similarities, complementing traditional mammalian models and serving as a valuable tool for genetic screening and drug discovery. In this comprehensive review, we highlight various drug delivery techniques and systems employed for therapeutic interventions of neurological diseases in zebrafish, and evaluate their suitability. We also discuss the challenges encountered during this process and present potential advancements in innovative techniques.

A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity.

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.