Investigation of LPIN1 and its Substrate, Phosphatidic Acid, as Modifiers of Niemann-Pick Type C disease

Niemann-Pick type C (NP-C) disease is a neurodegenerative disease with a typically paediatric onset, for which no satisfactory cure is available. Inheritance of two dysfunctional copies of either cholesterol transport gene NPC1 or NPC2 perpetrates substantial accumulation of sterols and secondary lipids within the lysosome, eventuating in devastating and progressive visceral and neurological symptoms. Although the disease is ostensibly monogenic, there is an impressive diversity among sufferers of the disease in regards to onset of disease, specific symptoms imposed and prognosis. Recently, genetic modifiers of the NP-C disease have been reported in several models, which have improved understanding of the disease and identified new targets for treatment. Accordingly, the relevance of the LPIN1 gene and the phosphatidic acid phosphatase activity of its enzyme, were investigated for their ability to modify the NP-C phenotype in a fibroblast and mouse model. Treatment of NP-C fibroblasts with inhibition of phosphatidic acid-generating enzymes DGK and PLD was ineffective in reducing the lysosomal accumulation of cholesterol. Likewise, Npc1-/-Lpin1-/- mice were largely indistinguishable from Npc1-/-, Lpin1-/- and wild-type mice at P0 for brain and liver lipid profiles, cerebellar histology and liver autophagy.