CLN3 deficiency leads to neurological and metabolic perturbations during early development

Abstract

Juvenile neuronal ceroid lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 yr and is most commonly caused by mutations in the highly conservedCLN3gene. Here, we generatedcln3morphants and stable mutant lines in zebrafish. Although neither morphant nor mutantcln3larvae showed any obvious developmental or morphological defects, behavioral phenotyping of the mutant larvae revealed hyposensitivity to abrupt light changes and hypersensitivity to pro-convulsive drugs. Importantly, in-depth metabolomics and lipidomics analyses revealed significant accumulation of several glycerophosphodiesters (GPDs) and cholesteryl esters, and a global decrease in bis(monoacylglycero)phosphate species, two of which (GPDs and bis(monoacylglycero)phosphates) were previously proposed as potential biomarkers forCLN3disease based on independent studies in other organisms. We could also demonstrate GPD accumulation in human-induced pluripotent stem cell–derived cerebral organoids carrying a pathogenic variant forCLN3. Our models revealed that GPDs accumulate at very early stages of life in the absence of functional CLN3 and highlight glycerophosphoinositol and BMP as promising biomarker candidates for pre-symptomaticCLN3disease.