Background CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of…

imageimageLoss of Batten disease-associated lysosomal protein CLN3 leads to DNA damage and activation of c-Abl-YAP1-dependent pro-apoptotic signaling which underlies increased apoptosis susceptibility...

Purpose: CLN3 disease is a lysosomal storage disorder that leads to retinal degeneration. CLN3 disea

Batten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in the CLN3 gene encoding a lysosomal protein. There are currently no therapies targeting the progression of the disease, mostly due to the lack of knowledge about the disease mechanisms. To gain insight into the impact of CLN3 loss on cellular signaling and organelle function, we generated CLN3 knock-out cells in a human cell line (CLN3-KO), and performed RNA sequencing to obtain the cellular transcriptome. Following a multi-dimensional transcriptome analysis, we identified the transcriptional regulator YAP1 as a major driver of the transcriptional changes observed in CLN3-KO cells. We further observed that YAP1 pro-apoptotic signaling is hyperactive as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of CLN3exΔ7/8 mice, an established model of Batten disease. Loss of CLN3 activates YAP1 by a cascade of events that starts with the inability of releasing glycerophosphodiesthers from CLN3-KO lysosomes, which leads to perturbations in the lipid content of the nuclear envelope and nuclear dysmorphism. This results in increased number of DNA lesions, activating the kinase c-Abl, which phosphorylates YAP1, stimulating its pro-apoptotic signaling. Altogether, our results highlight a novel organelle crosstalk paradigm in which lysosomal metabolites regulate nuclear envelope content, nuclear shape and DNA homeostasis. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may open new c-Abl-centric therapeutic strategies to target Batten disease. ### Competing Interest Statement The authors have declared no competing interest.

Gene therapy to treat CLN3 disease neuromuscular manifestations  BioWorld MedTech

Background: Microglia are the primary brain cell type regulating neuroinflammation and they are impo

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Batten disease is characterized by early-onset blindness, juvenile dementia and death during the sec

CLN3 disease causes profound neurological deficits in affected children, but less well recognized are a variety of peripheral neuromuscular and gastrointestinal problems. We hypothesized that in addit...

Batten disease is characterized by early-onset blindness, juvenile dementia and death during the sec

Background: Microglia are the primary brain cell type regulating neuroinflammation and they are impo