Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway
Abstract According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8 -knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.
Authors
- Ulrich Stelzl (ORCID: https://orcid.org/0000-0003-2500-3585)
- Carina Wagner (ORCID: https://orcid.org/0000-0002-0146-702X)
- Nermeen Fawzy (ORCID: https://orcid.org/0009-0003-2376-947X)
- Ulrike Taschler (ORCID: https://orcid.org/0000-0001-9000-1602)
- Achim Lass (ORCID: https://orcid.org/0000-0002-8190-7151)
- G Grabner (ORCID: https://orcid.org/0000-0002-7110-9957)
- Kasparas Petkevicius (ORCID: https://orcid.org/0000-0003-2295-6065)
- Dagmar Kratky (ORCID: https://orcid.org/0000-0003-1357-7573)
- Clemens Hofmann (ORCID: https://orcid.org/0009-0007-9891-7149)
- Dominik Bulfon (ORCID: https://orcid.org/0000-0001-7628-7368)
- Robert Zimmermann (ORCID: https://orcid.org/0000-0002-7354-870X)
- Lennart Hartig (ORCID: https://orcid.org/0000-0002-2905-6476)
- Martin Tischitz (ORCID: https://orcid.org/0009-0009-0397-1228)
- Anita Pirchheim
- Rolf Breinbauer (ORCID: https://orcid.org/0000-0001-6009-7359)
- Clara Zitta (ORCID: https://orcid.org/0009-0009-5494-5441)
- Johannes Breithofer (ORCID: https://orcid.org/0000-0002-4804-1341)
- Keira Turner
Institutions
- University of Graz (AT)
- Medical University of Graz (AT)
- University of Cambridge (GB)
- Graz University of Technology (AT)
- BioTechMed-Graz (AT)
- Danish Cancer Society (DK)
- MRC Mitochondrial Biology Unit (GB)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-09-15
- DOI
- https://doi.org/10.1038/s41556-026-02059-8
- Citations
- 2
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 10.24