Authors: Vodicka, Petr | Mo, Shunyan | Tousley, Adelaide | Green, Karin M. | Sapp, Ellen | Iuliano, Maria | Sadri-Vakili, Ghazaleh | Shaffer, Scott A. | Aronin, Neil | DiFiglia, Marian | Kegel-Gleason, Kimberly B.
Background: Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG expansion in the HD gene, which encodes the protein Huntingtin. Huntingtin associates with membranes and can interact directly with glycerophospholipids in membranes. Objective: We analyzed glycerophospholipid profiles from brains of 11 month old wild-type (WT) and Q140/Q140 HD knock-in mice to assess potential changes in glycerophospholipid metabolism. Methods: Polar lipids from cerebellum, cortex, and striatum were extracted and analyzed by liquid chromatography and negative ion electrospray tandem mass spectrometry analysis (LC-MS/MS). Gene products involved in polar lipid metabolism were studied
…using western blotting, immuno-electron microscopy and qPCR. Results: Significant changes in numerous species of glycerophosphate (phosphatidic acid, PA) were found in striatum, cerebellum and cortex from Q140/Q140 HD mice compared to WT mice at 11 months. Changes in specific species could also be detected for other glycerophospholipids. Increases in species of lyso-PA (LPA) were measured in striatum of Q140/Q140 HD mice compared to WT. Protein levels for c-terminal binding protein 1 (CtBP1), a regulator of PA biosynthesis, were reduced in striatal synaptosomes from HD mice compared to wild-type at 6 and 12 months. Immunoreactivity for CtBP1 was detected on membranes of synaptic vesicles in striatal axon terminals in the globus pallidus. Conclusions: These novel results identify a potential site of molecular pathology caused by mutant Huntingtin that may impart early changes in HD.
Keywords: Huntington’s disease, Huntingtin, glycerophospholipid, mass spectrometry, phosphatidic acid, acyl transferase, lipidomics, CtBP, LPAAT, phospholipase, LPA
Citation: Journal of Huntington's Disease,
vol. 4, no. 2, pp. 187-201, 2015
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