title: Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington's Disease: A Targeted GC-MS/MS Sterol Analysis.
abstract: BACKGROUND
  Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood.
  
  
  OBJECTIVE
  This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice.
  
  
  METHODS
  GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests.
  
  
  RESULTS
  24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes.
  
  
  CONCLUSIONS
  Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia.|School of Biological Sciences, University of Wollongong, NSW, Australia.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kreilaus
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia.|School of Biological Sciences, University of Wollongong, NSW, Australia.
authors.forename: Adena S
authors.initials: AS
authors.lastname: Spiro
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkvillie, VIC, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia.|School of Biological Sciences, University of Wollongong, NSW, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia.|School of Biological Sciences, University of Wollongong, NSW, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Jenner
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000068079:Motor Disorders / Q000503:physiopathology; D013261:Sterols / Q000378:metabolism*
chemical_list: D013261:Sterols; D002784:Cholesterol
keywords: 24-hydroxycholesterol; Huntington’s disease; biological markers; cholesterol; cholesterol 24-hydroxylase; tandem mass spectrometry