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Neurotherapeutics. 2016 Jul;13(3):614-22. doi: 10.1007/s13311-016-0427-5.

Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status.

Author information

1
Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
2
Neuropsychiatry Unit, Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, Melbourne, Victoria, 3050, Australia.
3
Statistics and Informatics Platform, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
4
School of Mathematics and Geospatial Sciences, RMIT University, Melbourne, Victoria, 3000, Australia.
5
Neurotherapeutics Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
6
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia.
7
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, 3010, Australia.
8
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria, 3010, Australia.
9
Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia. ashley.bush@florey.edu.au.

Abstract

Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP-C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 (+/-) mice by 9 weeks of age. Relative to Npc1 (+/+) mice, Npc1 (+/-) mice failed to show neurodevelopmental improvements in motor coordination and balance on an accelerating Rotarod. In the open-field test, Npc1 (+/-) mice showed an intermediate phenotype in spontaneous locomotor activity compared with Npc1 (+/+) and Npc1 (-/-) mice, as well as decreased center tendency. Together with increased stride length under anxiogenic conditions on the DigiGait treadmill, these findings are consistent with heightened anxiety. Our findings indicate that pathogenic NPC1 allele carriers, who represent about 0.66 % of humans, could be vulnerable to motor and anxiety disorders.

KEYWORDS:

Carrier; Heterozygote disease; NPC1; Neurological; Niemann–Pick disease type C; haploinsufficiency

PMID:
26942423
PMCID:
PMC4965399
DOI:
10.1007/s13311-016-0427-5
[Indexed for MEDLINE]
Free PMC Article

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