title: Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.
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. (59)Fe 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.
authors.affiliation: Landon Center on Aging, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 1005, Kansas City, KS, 66160, USA.|Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3030, Kansas City, KS, 66160, USA.|Neuroscience Graduate Program, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3038, Kansas City, KS, 66160, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Stroh
authors.affiliation: Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3051, Kansas City, KS, 66160, USA.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Winter
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3030, Kansas City, KS, 66160, USA.|Neuroscience Graduate Program, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3038, Kansas City, KS, 66160, USA.|Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd., MSN 2012, Kansas City, KS, 66160, USA.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.affiliation: Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3051, Kansas City, KS, 66160, USA.|Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 1018, Kansas City, KS, 66160, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: McCarson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3030, Kansas City, KS, 66160, USA. hzhu@kumc.edu.|Neuroscience Graduate Program, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 3038, Kansas City, KS, 66160, USA. hzhu@kumc.edu.|Department of Clinical Laboratory Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 4048G-Eaton, Kansas City, KS, 66160, USA. hzhu@kumc.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism*; D042966:Cytochrome-B(5) Reductase / Q000235:genetics* / Q000378:metabolism; D006246:Harmaline; D006706:Homeostasis / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D014202:Tremor / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism
chemical_list: D006246:Harmaline; D007501:Iron; C488723:Ncb5or protein, mouse; D042966:Cytochrome-B(5) Reductase
keywords: Cerebellum; Iron; Locomotion; Metabolism; Tremor