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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.

Original publication




Journal article


Behav Brain Res

Publication Date





213 - 223


Ataxia, Circadian, Lysosome storage disorder, Mouse mutant, Actigraphy, Animals, CLOCK Proteins, Cholesterol, Circadian Rhythm, Disease Models, Animal, Fluorescent Antibody Technique, Mice, Inbred BALB C, Mice, Knockout, Motor Activity, Niemann-Pick Disease, Type C, Photoperiod, Proteins, Retina, Rod Opsins, Sandhoff Disease, Suprachiasmatic Nucleus, Transcription Factor Brn-3A, beta-N-Acetylhexosaminidases