Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice
| Autor: | Michelle K. Winter, Russell H. Swerdlow, Hao Zhu, Kenneth E. McCarson, Matthew A. Stroh |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cerebellum Iron Context (language use) Motor Activity Biology Harmaline Biochemistry Article Midbrain Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Mesencephalon Internal medicine Tremor Conditional gene knockout medicine Animals Homeostasis Mice Knockout Behavior Animal Metabolism Iron deficiency medicine.disease Mitochondria Cytosol 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Neurology (clinical) Neuroscience Cytochrome-B(5) Reductase 030217 neurology & neurosurgery |
| Zdroj: | Metabolic Brain Disease. 31:951-964 |
| ISSN: | 1573-7365 0885-7490 |
| DOI: | 10.1007/s11011-016-9834-x |
| Popis: | 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 weeks 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. |
| Databáze: | OpenAIRE |
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