Multi-omics reveal phosphatidic acid phosphatases modify Niemann-Pick type C disease severity.

Niemann-Pick type C (NP-C) disease is a fatal, neurodegenerative disorder caused by lysosomal lipid accumulation with variable symptomatic penetrance at the primary disease locus encoded by the NPC1 gene. We identified genetic modifiers of disease progression by integrating genetic, genomic, and lipidomic analyses across yeast, mice, and human patients. A yeast screen identified 45 candidate modifiers of disease severity, including phosphatidic acid hydrolase (PAH1), a key enzyme in triacylglycerol (TAG) synthesis. Lipidomic profiling of liver, cerebral cortex, and cerebellum from Npc1 -/- mice at multiple ages demonstrated that dysregulation of TAG metabolism strongly correlates with disease progression. Deletion of the murine PAH1 orthologues Lpin1 or Lpin2 in Npc1 -/- mice reduced lifespan, accelerated Purkinje cell loss, and increased hepatic lipid accumulation. In NP-C patients, two LPIN3 variants were associated with early childhood onset. These findings identify lipins as modifiers of NP-C disease and expand our understanding of lipid metabolism in neurodegeneration.