CLN3 is required for the clearance of glycerophosphodiesters from lysosomes

Nouf N. Laqtom, Wentao Dong, Uche N. Medoh, Andrew L. Cangelosi, Vimisha Dharamdasani, Sze Ham Chan, Tenzin Kunchok, Caroline A. Lewis, Ivonne Heinze, Rachel Tang, Christian Grimm, An N. Dang Do, Forbes D. Porter, Alessandro Ori, David M. Sabatini and Monther Abu-Remaileh ()
Additional contact information
Nouf N. Laqtom: Stanford University
Wentao Dong: Stanford University
Uche N. Medoh: Stanford University
Andrew L. Cangelosi: Massachusetts Institute of Technology
Vimisha Dharamdasani: Whitehead Institute for Biomedical Research
Sze Ham Chan: Whitehead Institute for Biomedical Research
Tenzin Kunchok: Whitehead Institute for Biomedical Research
Caroline A. Lewis: Whitehead Institute for Biomedical Research
Ivonne Heinze: Leibniz Institute on Aging—Fritz Lipmann Institute
Rachel Tang: Ludwig-Maximilians-Universität
Christian Grimm: Ludwig-Maximilians-Universität
An N. Dang Do: Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
Forbes D. Porter: Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
Alessandro Ori: Leibniz Institute on Aging—Fritz Lipmann Institute
Monther Abu-Remaileh: Stanford University

Nature, 2022, vol. 609, issue 7929, 1005-1011

Abstract: Abstract Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus1. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs)2–4. For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05221-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:609:y:2022:i:7929:d:10.1038_s41586-022-05221-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05221-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().