The Batten disease protein CLN8 is a stereospecific acyltransferase in bis(monoacylglycero)phosphate biosynthesis
Abstract Loss-of-function mutations in the endoplasmic reticulum membrane protein CLN8 cause Batten disease, a neurodegenerative lysosomal storage disorder. CLN8 acts with the lysosomal enzyme CLN5 to produce bis(monoacylglycero)phosphate (BMP), a signature lysosomal phospholipid with unique S , S stereochemistry. However, the role of CLN8 in this pathway has remained unclear. Here we establish that CLN8 is a glycerophosphoglycerol acyltransferase that catalyses the stereospecific acylation of S , S -glycerophosphoglycerol to generate S , S -lysophosphatidylglycerol, the CLN5 substrate in BMP synthesis. Cryo-electron microscopy structures define the CLN8 active site and support a ping-pong acyl transfer mechanism. Batten disease mutations impair CLN8 enzymatic activity and abolish BMP production in mice. Exogenous S , S -lysophosphatidylglycerol, but not the R , S stereoisomer, restores BMP synthesis in CLN8-deficient cells and mice and improves neurological phenotypes in cln8 mutant zebrafish. These findings define the function of CLN8, explain the biochemical basis of CLN8 Batten disease and establish BMP precursor supplementation as a proof-of-concept therapeutic strategy.
Authors
- Jonathan J. Ruprecht (ORCID: https://orcid.org/0000-0002-1838-7245)
- Denis Lacabanne (ORCID: https://orcid.org/0000-0002-8911-3794)
- Albert Koulman (ORCID: https://orcid.org/0000-0001-9998-051X)
- Andrew M. James (ORCID: https://orcid.org/0000-0002-0515-9649)
- Jill M. Weimer (ORCID: https://orcid.org/0000-0003-2504-4942)
- Benjamin Jenkins (ORCID: https://orcid.org/0000-0003-0038-9709)
- Kasparas Petkevicius (ORCID: https://orcid.org/0000-0003-2295-6065)
- Pradeep Kumar Sheokand (ORCID: https://orcid.org/0000-0002-0846-3398)
- Chak Shun Yu (ORCID: https://orcid.org/0009-0004-3106-9681)
- Michael P. Murphy (ORCID: https://orcid.org/0000-0003-1115-9618)
- Antti M. Salo (ORCID: https://orcid.org/0000-0003-2085-7880)
- Edmund R.S. Kunji (ORCID: https://orcid.org/0000-0002-0610-4500)
- Clarissa D. Booth
- Martin King (ORCID: https://orcid.org/0000-0001-6030-5154)
- Maria Marchese (ORCID: https://orcid.org/0000-0002-0194-0702)
- Stefania Della Vecchia (ORCID: https://orcid.org/0000-0002-2066-2162)
- Jessica Müller-Niva
- Susannah K. Leese
- Joris van der Kleij
- Reetta Hinttala
- Johanna Uusimaa
- Keira Turner
- Nidhi Juneja (ORCID: https://orcid.org/0009-0008-6343-5120)
- Filippo M. Santorelli
Institutions
- University of South Dakota (US)
- University of Cambridge (GB)
- Oulu University Hospital (FI)
- Sanford Research (US)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Fondazione Stella Maris (IT)
- University of Florence (IT)
- MRC Mitochondrial Biology Unit (GB)
- University of Oulu (FI)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-09-15
- DOI
- https://doi.org/10.1038/s41556-026-02061-0
- Citations
- 2
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 10.24