CLN5 deficiency impairs glucose uptake in Batten disease

Abstract

CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in the CLN5 gene encoding the lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and lysosomal function. Limited knowledge of cellular mechanisms and unclear drug targets hinder translating this to childrens treatment, which remains symptomatic. We developed and characterized a new cln5 knock-out zebrafish model that replicates key features and molecular signatures of the human disease. Loss of Cln5 function in vivo altered axonal growth of retinal ON-bipolar cells revealing new disease features. Additionally, multi-omic analyzes at different developmental stages, revealed an impaired glucose metabolism as an original finding in NCL. This work demonstrates the profound metabolic impact of CLN5 dysfunction, offering a promising avenue toward targeted therapies for juvenile dementia.