CLN3 deficiency leads to neurological and metabolic perturbations during early development

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a rare, autosomal recessive neurodegenerative disorder primarily affecting children.
• Mutations in the CLN3 gene are the most common cause of this debilitating condition.
• Early diagnosis is crucial for managing Batten disease, but effective biomarkers are lacking.

Purpose of the Study:

• To investigate the molecular and metabolic changes associated with CLN3 gene mutations.
• To identify potential biomarkers for early, pre-symptomatic diagnosis of CLN3-related Batten disease.
• To develop and validate zebrafish and human organoid models for studying CLN3 disease.

Main Methods:

• Generation of cln3 morphant and stable mutant zebrafish lines.
• Behavioral phenotyping of mutant zebrafish larvae.
• Comprehensive metabolomics and lipidomics analyses.
• Generation of human-induced pluripotent stem cell-derived cerebral organoids with CLN3 pathogenic variants.

Main Results:

• Zebrafish models exhibited no overt developmental defects but showed altered light sensitivity and seizure susceptibility.
• Significant accumulation of glycerophosphodiesters (GPDs) and cholesteryl esters, with a decrease in bis(monoacylglycero)phosphate species, was observed.
• GPDs were also found to accumulate in human CLN3 cerebral organoids.
• GPDs accumulate early in the absence of functional CLN3, suggesting their potential as pre-symptomatic biomarkers.

Conclusions:

• Glycerophosphodiesters (GPDs), particularly glycerophosphoinositol and bis(monoacylglycero)phosphates, are promising biomarker candidates for early CLN3 Batten disease detection.
• Zebrafish and human organoid models provide valuable tools for studying CLN3 disease mechanisms and biomarker discovery.
• Early metabolic alterations, specifically GPD accumulation, precede overt symptoms in CLN3 disease.