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Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway

ABSTRACT: According to our current knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to produce 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 (GPG), resulting in the formation of lysophosphatidylglycerol (LPG). The acyltransferase reaction is catalyzed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived LPG is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis, but not into phosphatidylglycerol and cardiolipin. CLN8-knockout cells and mice cannot utilize GPG 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Epithelial Cell, Promonocyte

DISEASE(S): Neuronal Ceroid Lipofuscinosis 8,Neuronal Ceroid Lipofuscinosis

SUBMITTER: Ulrich Stelzl

LAB HEAD: Ulrich Stelzl

PROVIDER: PXD081638 | Pride | 2026-08-04

REPOSITORIES: Pride

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			Action	DRS
	CLN8_251107_gg_tab.txt	Txt
	CLN8_251107_report.log.txt	Txt
	CLN8_251107_sample_tab.txt	Txt
	HAP1CLN8_KO1_BA7_1_17430.d.zip	Other
	HAP1CLN8_KO2_BA8_1_17432.d.zip	Other

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The Batten disease gene product CLN3 is required for the efflux of glycerophosphodiesters from lysosomes

Project description:The lysosome has many cellular roles, including degrading and recycling macromolecules and signaling to the mTORC1 growth regulator. Lysosomal dysfunction occurs in various human diseases, including common neurodegenerative diseases as well as monogenic lysosomal storage disorders (LSDs). For most LSDs the causal genes have been identified, but in many cases the function of the implicated gene is unknown. Here, we develop the LysoTag mouse line for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We apply it to the study of CLN3, a lysosomal transmembrane protein of unclear function whose loss 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 stable isotope tracing experiments show that CLN3 is required for their lysosomal egress. Loss of CLN3 also alters upstream glycerophospholipid catabolism in the lysosome. Our results suggest that CLN3 is a lysosomal effluxer of GPDs and reveal Batten disease as the first, to our knowledge, neurodegenerative LSD with a primary defect in glycerophospholipid metabolism.

2022-07-11 | PXD018624 | Pride

Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lysomitochondrial dysfunction, and lipid dyshomeostasis

Project description:Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses,and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of age and CLN1 lipofuscin to be remarkably similar. Dissection of implicated molecular pathways reveals protein Sacylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, >95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.

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Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by Pla2g15

Project description:Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of TFEB in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB binding sites of lysosomal genes and determined that the phospholipase Pla2g15 regulates BMP lipid catabolism. Knockdown of Pla2g15 in mice increased BMP lipid levels, ablated the cold-induced rise, and improved cold tolerance. Knockout of Pla2g15 in mice and hepatocytes led to increased BMP lipid levels, that were decreased with re-expression of Pla2g15. Mutation of the catalytic site of Pla2g15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through Pla2g15 catabolism.

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Identification of lysosomal phospholipases in context of Batten disease Cln3

Project description:Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. The loss of CLN3 leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage upon CLN3 loss being robustly detected across species, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome. Mechanistically, we found that GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity and the latter of which is identified in this study. Interestingly, GPDs show more potency in inhibiting the rate-limiting lysophospholipase activity of these lipases. Consistent with our biochemical data, loss of CLN3 and sequestration of GPDs lead to the accumulation of toxic lysophospholipids, intermediates in lipid degradation, in lysosomes of CLN3-deficient cells and tissues. This work provides novel insights into lysosomal phospholipid catabolism and 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.

2023-08-23 | MSV000092731 | MassIVE

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Project description:Complex lipid metabolism plays a crucial role in regulating aging. We recently discovered that the phospholipid bis(monoacylglycero)phosphate (BMP) increases in aged human muscles and many mouse tissues. The phospholipase PLA2G15 is reportedly involved in BMP synthesis, however, its specific role in aging remains unknown. To elucidate the role of PLA2G15 in aging, we used C. elegans as a model. When silencing plag-15, the predicted worm orthologue of PLA2G15, we observed improved healthspan and lifespan extension. Semi-targeted lipidomics highlighted that instead of changes related to BMP, plag-15 RNAi led to lower levels of lysophosphatidic acid, lysophosphatidylcholine and lysophosphatidylethanolamine. Transcriptome-guided epistasis experiments identified that the lifespan extension of plag-15 RNAi worms is regulated by transcription factors hlh-30 and elt-3, and lysosomal vitamin B12 transporter pmp-5 (human TFEB, GATA, and ABCD4 respectively). Overall, we conclude that targeting phospholipid remodeling through plag-15 could be a promising strategy to promote healthy aging.

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