title: Mass Spectrometry Analysis of Wild-Type and Knock-in Q140/Q140 Huntington's Disease Mouse Brains Reveals Changes in Glycerophospholipids Including Alterations in Phosphatidic Acid and Lyso-Phosphatidic Acid.
abstract: 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.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, MA, USA.
authors.forename: Shunyan
authors.initials: S
authors.lastname: Mo
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Tousley
authors.affiliation: Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, MA, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Green
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Iuliano
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.affiliation: Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, MA, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Departments of Medicine and Cell and Developmental Biology, UMASS Medical School, Worcester, MA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Kegel-Gleason
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D020404:Glycerophospholipids / Q000378:metabolism*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010712:Phosphatidic Acids / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020404:Glycerophospholipids; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D010712:Phosphatidic Acids; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C032881:lysophosphatidic acid
keywords: CtBP; Huntingtin; Huntington’s disease; LPA; LPAAT; acyl transferase; glycerophospholipid; lipidomics; mass spectrometry; phosphatidic acid; phospholipase