A deficit in zinc availability can cause alterations in tubulin thiol redox status in cultured neurons and in the developing fetal rat brain

Abstract

Zinc (Zn) deficiency during early development can result in multiple brain abnormalities and altered neuronal functions. 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 paper, we tested the hypothesis that oxidative stress is involved in Zn deficiency-induced altered tubulin dynamics and the associated dysregulation of transcription factor NF-κB. For this purpose, we used two cell culture models (rat cortical neurons, human IMR-32 neuroblastoma cells) and an animal model of Zn deficiency. A low rate of in vitro tubulin polymerization, an increase in tubulin oligomers and a higher protein cysteine oxidation were observed in the Zn deficient neuronal cells, and in gestation day 19 fetal brains obtained from dams fed marginal Zn diets throughout pregnancy. These alterations could be prevented by treating the Zn deficient cells with the reducing agent tris(2-carboxyethyl)phosphine, or the presence of N-acetyl cysteine (NAC) and α-lipoic acid (LA). Consistent with the above, Zn deficiency-induced tubulin-mediated alterations in transcription factor NF-κB nuclear translocation were prevented by treating IMR-32 cells with LA and NAC. Binding of the NF-κB protein p50, dynein and karyopherin alpha (components of the NF-κB transport complex) to β-tubulin as well as the expression of NF-κB dependent genes (bcl-2, cyclin D1 and c-myc) were also restored by the addition of LA and NAC to Zn deficient cells. In conclusion, a deficit in Zn viability could affect early brain development through: 1) an induction of oxidative stress; 2) tubulin oxidation; 3) altered tubulin dynamics, and 4) deregulation of signals (e.q. NF-κB) involved in critical developmental events.

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

“…Cellular zinc deficiency increases single-strand DNA breaks and leads to activation of DNA repair enzymes like p53 [15,36]. Zinc is a key regulator of cellular redox homeostasis [37], and zinc deficiency leads to accumulation of reactive oxygen species that damage DNA and oxidize protein thiols including those in tubulin resulting in disruption of the cytoskeleton [38]. Reduced proliferation and increased apoptosis may be important mechanisms to conserve zinc and prevent the formation of neurons with damaged DNA and dysfunctional proteins.…”

Zinc and the aging brain

“…Zinc deficiency also facilitates calcium influx through the NMDAR leading to activation of NADPH oxidase and nitric oxide synthase (Aimo et al 2010). Activation of these enzymes combined with mitochondrial dysfunction leads to oxidative stress and subsequent disruption of microtubule stability (Mackenzie et al 2011) and accumulation of phosphorylated Tau in NFT (Bonda et al 2011a). Zinc also regulates degradation of Ab directly through modulation of protease structure and indirectly by increasing protease expression (Grasso et al 2012).…”

Zinc and the ERK Kinases in the Developing Brain

“…In rats that were fed a marginal zinc diet during gestation, no obvious alterations in maternal and fetal outcome were observed (Aimo et al 2010b). However, altered protein thiol homeostasis, tubulin oxidation, and impaired tubulin polymerization were observed in brains from marginally zinc deficient fetuses at embryonic day (E) 19 (Mackenzie et al 2011). Furthermore, several signaling cascades, including ERK1/2, are affected by marginal zinc deficiency at E19 (Aimo et al 2010b).…”

“…Nevertheless, oxidative stress may affect other aspects of ERK1/2 modulation. In zinc deficient cells, tubulin oxidation and impaired polymerization affect the microtubule-dependent nuclear transport of transcription factor NF-κB (Mackenzie et al 2011). Given that ERK1/2 bind to microtubules (Reszka et al 1995), zinc deficiency-induced alterations of the cytoskeleton could affect ERK1/2 activity and nuclear transport.…”