A decrease in zinc availability causes tubulin oxidation leading to impaired NF-¨ºB nuclear transport in neurons and in the developing brain

SALVADOR GABRIELA; MACKENZIE GERADO; CARL KEEN; OTEIZA PATRICIA

San PAblo

Congreso; VII Meeting of the SFRBM South American Group; 2011

SFRBM

Gabriela Salvador1, Gerardo G. Mackenzie2,3 , Carolina Romero2,3, Carl L. Keen2  and Patricia I. Oteiza2,3 1 INIBIBB ¨CCONICET., Universidad Nacional del Sur, Bah¨ªa Blanca 8000, Argentina. 2 Departments of Nutrition and 3Environmental Toxicology, University of California Davis, CA 95616, USA.   In multiple species, including humans, zinc (Zn) deficiency during early development has been reported to result in multiple brain malformations and altered neuronal function. In rats, a gestational deficit of Zn can affect the fetal brain cytoskeleton, and signaling cascades involved in cellular processes that are central to brain development. In the current work, using two cell culture models (rat cortical neurons, human IMR-32 neuroblastoma cells) and a pregnant rat model, we tested the hypothesis that oxidative stress is involved in Zn deficiency-induced altered tubulin dynamics and the associated dysregulation of transcription factor NF-¦ÊB.   A low rate of in vitro tubulin polymerization, an increase in tubulin oligomers, and a higher extent of protein cysteine oxidation were observed in the Zn deficient neuronal cells, as well as  in gestation day 19 fetal brains obtained from dams fed low Zn diets throughout pregnancy. Treating the Zn deficient cells with N-acetyl cysteine (NAC) and ¦Á-lipoic acid (LA) attenuated these effects.  Additionally, Zn deficiency-induced tubulin-mediated alterations in transcription factor NF-¦ÊB nuclear translocation did not occur in IMR-32 cells supplemented with LA and NAC. Binding of the NF-¦ÊB protein p50, dynein and karyopherin alpha to ¦Â-tubulin as well as the expression of NF-¦ÊB dependent genes (bcl-2, cyclin D1 and c-myc) in the Zn deficient cells were restored by the addition of LA and NAC. We suggest a deficit in Zn affects early brain development through: 1) an induction of oxidative stress; 2) tubulin oxidation; 3) altered tubulin dynamics, and 4) a deregulation of signals involved in critical developmental events.