Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Batten disease is a fatal neurodegenerative disorder with no current therapies.
• Mutations in the CLN3 gene are the most common cause of Batten disease.
• The molecular mechanisms driving CLN3 loss-related pathology are poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which CLN3 loss impacts cellular signaling.
• To identify key molecular players involved in the pathogenesis of Batten disease.
• To explore potential therapeutic targets for Batten disease.

Main Methods:

• Generated human CLN3 knock-out (CLN3-KO) cells.
• Performed RNA-sequencing (RNA-seq) analysis on CLN3-KO cells.
• Investigated CLN3 loss effects in retinal pigment epithelia cells and Cln3^Δ7/8 mouse models.

Main Results:

• Transcriptional analysis identified YAP1 as a key regulator in CLN3-KO cells.
• CLN3 loss increases YAP1-mediated pro-apoptotic signaling in various cell types and tissues.
• CLN3 deficiency causes DNA damage, activating c-Abl kinase, which phosphorylates YAP1 and enhances pro-apoptotic signaling.

Conclusions:

• A novel molecular pathway involving CLN3, DNA damage, c-Abl, and YAP1 in Batten disease pathogenesis has been identified.
• This mechanism explains how CLN3 functional loss leads to cellular dysfunction and apoptosis.
• Targeting the c-Abl/YAP1 axis presents a potential therapeutic strategy for Batten disease.