Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response.

Overview

1. Department of Microbiology, Oslo University Hospital, Oslo, Norway
2. Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
3. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
4. Proteomics and Modomics Experimental Core Facility (PROMEC) at NTNU, and the Central Norway Regional Health Authority, Trondheim, Norway
5. Centre for Embryology and Healthy Development, University of Oslo, 0373 Oslo, Norway

Abstract

Background: CLN3 Batten disease is a severe pediatric neurodegenerative disorder caused by mutations in the CLN3 gene, most commonly a 1 kb deletion encompassing exons 7 and 8. CLN3 deficiency is associated with lysosomal dysfunction, impaired cellular clearance and disrupted metabolism. While neurons are particularly vulnerable in CLN3 Batten disease and have been the primary focus of research, glial cells are increasingly recognized as active contributors to disease pathology. Among them, astrocytes—the most abundant glial cell type in the brain—play critical roles in maintaining neuronal health and homeostasis. However, astrocytes remain understudied in CLN3 patient-derived models.

Methods: We present the first iPSC-derived astrocyte model from a skin biopsy of a CLN3 patient carrying the common 1 kb deletion. Cellular and molecular features of iPSC and astrocytes derived from both healthy controls and the CLN3 patient were characterized via qPCR, immunocytochemistry and targeted mass spectrometry. In addition, comprehensive omics-based profiling, through transcriptomic and label-free quantitative proteomics, was performed to uncover novel molecular mechanisms and generate hypotheses that can guide future mechanistic and functional studies.

Results: Transcriptomic and proteomic analyses during astrocyte differentiation revealed an upregulation of mitochondrial respiratory chain complexes I and IV—contrasting with the downregulation typically observed in CLN3-deficient neurons. We also identified a metabolic shift favoring the elongation of very-long-chain saturated fatty acids, accompanied by reduced lipid synthesis and enhanced fatty acid oxidation. These metabolic alterations were paralleled by an upregulation of proteins involved in oxidative stress responses, likely reflecting a compensatory adaptation to mitochondrial and lipid metabolic dysregulation. Furthermore, we observed significant changes in chromatin organization during astrocyte differentiation in CLN3 cells, suggesting epigenetic remodeling as a contributing factor to disease pathology.

Conclusion: Our findings prompt the hypothesis that mitochondrial dysfunction may precede lysosomal defects in CLN3-deficient astrocytes. Restoring mitochondrial health could improve brain metabolism, inflammation control, neurotransmitter regulation, and neuronal survival, highlighting mitochondria as promising therapeutic targets in CLN3 Batten disease.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12929-026-01253-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32280600, at figshare; found in DataCite
• figshare:32280603, at figshare; found in DataCite
• uniprot.org/proteomes/up000005640, at UniProt; found in the text, “Data processing and analysis”

Availability of data and materials

The original uncropped version of western-blot analysis shown in Fig. 3F is provided in Supplementary Fig. 6.

Raw data files are available from the corresponding author(s) upon reasonable request and subject to institutional and ethical approvals. The LFQ MS data can be downloaded from the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD064202 following Reviewer account details: Username: : NxhB5U9jR14F.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 5 keywords, 13 MeSH terms, 1 funder, 71 references.

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This paper

Yang, M., Wang, W., Cámara-Quílez, M., Farsund, B. H., Andersen, N. N., Garten, K., Sharma, A., Lin, X., Åmellem, I., Ravlo, E., Ye, J., Bjørås, M., & de Sousa, M. M. L. (2026). Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response. Journal of biomedical science, 33(1), 50. https://doi.org/10.1186/s12929-026-01253-y

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