title: Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease.
abstract: Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1(nih)) and Sandhoff (Hexb knockout, Hexb(-/-)) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb(-/-) mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1(nih) mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level.
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Richardson
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Achilleas
authors.initials: A
authors.lastname: Livieratos
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Dumbill
authors.affiliation: Nuffield Department of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Hughes
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Gauri
authors.initials: G
authors.lastname: Ang
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Morris
authors.affiliation: Nuffield Department of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, UK.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Brown
authors.affiliation: Nuffield Department of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, UK.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Peirson
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Electronic address: kay.davies@dpag.ox.ac.uk.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Electronic address: peter.oliver@dpag.ox.ac.uk.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
mesh_terms: D056044:Actigraphy; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D047908:Intracellular Signaling Peptides and Proteins; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology / Q000503:physiopathology*; D017440:Photoperiod; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism; D012497:Sandhoff Disease / Q000473:pathology / Q000503:physiopathology*; D013493:Suprachiasmatic Nucleus / Q000473:pathology / Q000503:physiopathology*; D050819:Transcription Factor Brn-3A / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D056926:CLOCK Proteins; D002784:Cholesterol; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D017299:Rod Opsins; D050819:Transcription Factor Brn-3A; D001619:beta-N-Acetylhexosaminidases; D000099210:Melanopsin; C106831:Npc1 protein, mouse; C494189:Pou4f1 protein, mouse; C538944:Clock protein, mouse
keywords: Ataxia; Circadian; Lysosome storage disorder; Mouse mutant