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

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3<sup>Δ7/8</sup> mice, an established model of Batten disease. Loss of CLN3 leads to DNA damage, activating the kinase c-Abl which phosphorylates YAP1, stimulating its pro-apoptotic signaling. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may pave a way for novel c-Abl-centric therapeutic strategies to target Batten disease.

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Publication Details

Journal
EMBO Reports
Published
2025-11-06
DOI
https://doi.org/10.1038/s44319-025-00613-3
Primary Topic
Lysosomal Storage Disorders Research
Type
article
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article

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

Ira Milošević, Neuza Domingues, Ricardo Casqueiro, Nuno Raimundo et al.
EMBO Reports
Lysosomal Storage Disorders Research
article

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

Ira Milošević, Neuza Domingues, Ricardo Casqueiro, Nuno Raimundo, Tiago F. Outeiro, Niculin Joachim Herz, Henrique Girão, Ivan L. Salazar, Katarzyna Wieciorek, Andrea Ballabio, Tuong Huynh, Alessia Calcagnì, Joana Pires, Sofia Roque Freire
article en

Abstract

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3<sup>Δ7/8</sup> mice, an established model of Batten disease. Loss of CLN3 leads to DNA damage, activating the kinase c-Abl which phosphorylates YAP1, stimulating its pro-apoptotic signaling. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may pave a way for novel c-Abl-centric therapeutic strategies to target Batten disease.

EMBO ReportsVol. 26(24)
Centre for Human Genetics (GB), Baylor College of Medicine (US), Istituto Universitario di Studi Superiori di Pavia (IT), German Center for Neurodegenerative Diseases (DE), University of Oxford (GB), Universitätsmedizin Göttingen (DE), Neurological Research Institute (US), Federico II University Hospital (IT), Texas Children's Hospital (US), Telethon Institute Of Genetics And Medicine (IT), Max Planck Institute for Multidisciplinary Sciences (DE), University of Naples Federico II (IT), University of Coimbra (PT), Penn State Milton S. Hershey Medical Center (US), Newcastle University (GB)
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Lysosomal Storage Disorders Research
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