A loss of function zebrafish model of a new disease gene involved in cargo sorting and autophagy recapitulates patients’ axonopathy and cerebral atrophy and provides insights into disease mechanism

ID: 11805 The endosomal sorting complex for transport (ESCRT) machinery includes many subunits belonging to the complex I-III essential for multivesicular body cargo sorting and transport of ubiquitinylated transmembrane proteins to lysosomes for degradation, participating in autophagy. Manifesting the importance of these complexes in neurodevelopment, a number of knockout mouse models of various genes belonging to ESCRT complexes have demonstrated the causative link with several neurodevelopmental and neurodegenerative conditions, often associate to early embryo lethality. Here, we discuss the establishment of a transient zebrafish model of one of the subunits of the ESCRT complexes generated to model and study loss of function (LoF) mutations recently identified by whole exome sequencing recently in a new form of rare leukoencephalopathy with neurodevelopmental arrest, optic nerve and cerebral atrophy. Defects show varying severities in a court of patients collected internationally and harboring different gene variants. We show the early brain phenotyping of the zebrafish LoF model, established through a transient antisense oligonucleotide approach. The model recapitulates the global developmental delay, axonopathy and optic/cerebral atrophy observed in the disease, which is not rescued by the variants found in the patients, conversely to the wild-type form of the gene. The work allowed a quick validation of the pathogenicity of the candidate variants identified, useful for clinical purposes, such as disease identification and stratification. In addition, we show preliminary data on autophagy alteration and a first analysis of precursor cell behavior providing evidence that deficiency of this ESCRT subunit leads to impaired forebrain neurogenesis. In summary, our zebrafish disease model offers a tool to unveil mechanistic insights into a new leukoencephalopathy caused by a new disease gene leading to defective ESCRT function