Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease

Kwamina Nyame; Andy Hims; Aya Aburous; Nouf N Laqtom; Wentao Dong; Uche N Medoh; Julia C Heiby; Jian Xiong; Alessandro Ori; Monther Abu-Remaileh

doi:10.1016/j.molcel.2024.02.006

Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease

Mol Cell. 2024 Apr 4;84(7):1354-1364.e9. doi: 10.1016/j.molcel.2024.02.006. Epub 2024 Mar 5.

Authors

Affiliations

¹ Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.
² Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.
³ Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA; Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
⁴ Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
⁵ Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: monther@stanford.edu.

PMID: 38447580
PMCID: PMC10999246 (available on 2025-04-04)
DOI: 10.1016/j.molcel.2024.02.006

Abstract

Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.

Keywords: Batten disease; CLN3; GPDs; PLA2G15; PLBD2; glycerophosphodiesters; lysosomal storage disease; lysosome; neurodegeneration; phospholipase; phospholipid metabolism.

MeSH terms

Animals
Child
Glycerophospholipids / metabolism
Humans
Lysosomes / metabolism
Membrane Glycoproteins* / metabolism
Mice
Molecular Chaperones / metabolism
Neuronal Ceroid-Lipofuscinoses* / genetics
Neuronal Ceroid-Lipofuscinoses* / metabolism
Neuronal Ceroid-Lipofuscinoses* / pathology
Phospholipases / metabolism
Phospholipids / metabolism

Substances

Membrane Glycoproteins
Molecular Chaperones
Phospholipases
Glycerophospholipids
Phospholipids
CLN3 protein, human
CLN3 protein, mouse

Grants and funding

DP2 CA271386/CA/NCI NIH HHS/United States