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01-08-2016 | Original Article

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Authors: Matthew A. Stroh, Michelle K. Winter, Russell H. Swerdlow, Kenneth E. McCarson, Hao Zhu

Published in: Metabolic Brain Disease | Issue 4/2016

Abstract

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. ⁵⁹Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

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Wang WF, et al., NCB5OR deficiency causes anemia, iron dyshomeostasis and increased susceptibility to mitochondrial dysfunction. Manuscript in preparation;

Wang WF, et al., Monogenic NCB5OR diabetes is a result of impaired iron homeostasis and mitochondrial dysfunction in beta-cells. Manuscript in preparation;

Low-Fe is used in lieu of low-iron for figures.

Stroh MA, et al., NCB5OR deficiency in the cerebellum and midbrain affects fasted feeding behavior, thirst response, and voluntary exercise in mice. Publication in process.

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Title: Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice
Authors: Matthew A. Stroh
Michelle K. Winter
Russell H. Swerdlow
Kenneth E. McCarson
Hao Zhu
Publication date: 01-08-2016
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 4/2016
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-016-9834-x

Keynote webinar | Spotlight on sleep in brain health

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Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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