A groundbreaking study published in Nature by Nyame et al. unravels a promising new therapeutic target for Niemann-Pick disease type C1 (NPC1), a devastating lysosomal storage disorder. The researchers discovered that PLA2G15, an enzyme previously uncharacterized in the context of lysosomal lipid metabolism, functions as a bis(monoacylglycero)phosphate (BMP) hydrolase. Their findings demonstrate that genetic ablation of PLA2G15 in NPC1-deficient mice significantly mitigates neurodegeneration and visceral organ pathology, unveiling a new avenue for tackling lysosomal dysfunction with potential broad implications for other lysosomal storage diseases.
Niemann-Pick disease type C1 is a fatal neurovisceral disorder caused by mutations in the NPC1 gene, leading to the accumulation of cholesterol and various lipids within lysosomes. Patients suffer progressive neurological decline alongside systemic dysfunctions affecting the liver, spleen, and lungs. Despite increasing understanding of disease mechanisms, effective treatments remain elusive. The current study addresses a critical gap by identifying a novel enzyme that regulates BMP metabolism, a lipid class crucial for lysosomal membrane dynamics and function.
BMP lipids are unique anionic phospholipids predominantly enriched within the internal membranes of late endosomes and lysosomes. They play essential roles in membrane curvature, lipid sorting, and the activity of lysosomal hydrolases. Dysregulation of BMP homeostasis has been implicated in several lysosomal disorders; however, enzymes directly responsible for BMP degradation had not been definitively characterized until now. PLA2G15 emerges as a key player, catalyzing BMP hydrolysis and thereby influencing lysosomal lipid equilibrium.
Using a combination of in vitro biochemical assays and in vivo genetic models, the authors confirmed PLA2G15’s BMP hydrolase activity. To investigate therapeutic potential, the team generated PLA2G15 knockout mice and crossed them with the established Npc1^m1N/J mouse model, which recapitulates severe neurological and systemic NPC symptoms. Remarkably, PLA2G15 deficiency in the NPC1 background led to substantial amelioration of hallmark pathological features, indicating a beneficial impact of PLA2G15 inhibition on disease progression.
Disease biomarkers reinforced these observations. Neurofilament light chain (NfL), a well-validated marker of neurodegeneration measured in both cerebrospinal fluid and plasma, was significantly reduced in the double knockout mice compared to NPC1-deficient counterparts. Likewise, serum markers of liver damage, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), showed marked normalization, reflecting improved hepatic function following PLA2G15 ablation.
Interestingly, while NPC1-deficient mice exhibited increased BMP species, PLA2G15 depletion yielded only minor changes in BMP levels, suggesting nuanced regulation and possible compensatory mechanisms at play. Notably, cholesterol concentrations in brain and liver tissues remained unchanged despite genetic targeting, hinting that the therapeutic improvements stem not from correction of cholesterol accumulation but through modulation of secondary storage lipids.
Secondary lipid species, particularly sphingolipids and alkyl-lysophosphatidylcholine, known to accumulate in NPC1 disease, were significantly reduced in both cerebral and hepatic tissues when PLA2G15 was depleted. This reduction signifies a broader impact on lysosomal lipid metabolism, which may underlie the observed neuroprotective and systemic benefits.
At the cellular level, the study revealed profound rescue of cerebellar Purkinje neurons, a particularly vulnerable population in NPC1 pathology. Histopathological analyses demonstrated increased Purkinje cell survival and notable reductions in astrogliosis, microgliosis, and demyelination throughout the central nervous system. Such neural preservation translates into tangible functional improvements essential for patients’ quality of life.
Supporting the neurological findings, the effect of PLA2G15 deficiency extended to visceral organs. The extent of Kupffer cell hyperplasia within the liver and histiocytic proliferation in the spleen were both diminished. However, certain tissue alterations, such as hepatocyte vacuolation and pulmonary histopathology, remained unaffected, indicating partial organ-specific responses to enzyme inhibition.
Importantly, PLA2G15-deficient mice did not show any adverse lesions in the tissues analyzed, affirming the safety profile of genetic inhibition. Behaviorally, the compound knockout mice exhibited improved neurological composite scores, better motor coordination assessed via rotarod testing, and significantly prolonged survival compared to NPC1-deficient controls, underscoring the robust clinical relevance of targeting PLA2G15.
The authors posit that by attenuating lysosomal BMP hydrolysis, PLA2G15 depletion preserves BMP levels, thereby enhancing lysosomal functionality and reducing lysosomal stress. This effect appears to counteract the secondary lipid burden and cellular toxicity characteristic of lysosomal storage disorders like NPC1. The study’s integration of biochemical, histological, and behavioral data presents a comprehensive framework linking BMP metabolism to disease amelioration.
This work reveals an unprecedented therapeutic strategy for lysosomal diseases whereby targeting lipid metabolism enzymes modulates lysosomal membrane lipid composition and function. Given the centrality of lysosomal dysfunction across numerous neurodegenerative and metabolic disorders, PLA2G15 or its pathway components may represent a wider class of druggable targets beyond NPC1.
Future research will need to dissect the precise molecular mechanisms through which PLA2G15 regulates BMP turnover and to investigate potential small-molecule inhibitors that could replicate the genetic effects observed. Moreover, exploration of PLA2G15’s role across diverse cell types and lysosomal pathologies will illuminate its broader biological relevance and therapeutic potential.
In conclusion, Nyame et al. have uncovered PLA2G15 as a pivotal enzyme in lysosomal BMP metabolism whose genetic inactivation confers striking benefits in a mouse model of Niemann-Pick type C1 disease. This discovery not only advances our understanding of lysosomal lipid homeostasis but also charts a promising path toward novel treatments for devastating lysosomal storage diseases that currently lack effective therapies.
Subject of Research: Lysosomal lipid metabolism and therapeutic targeting in Niemann-Pick disease type C1.
Article Title: PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease.
Article References:
Nyame, K., Xiong, J., Alsohybe, H.N. et al. PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease. Nature (2025). https://doi.org/10.1038/s41586-025-08942-y
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