Heterozygous huntingtin promotes cadmium neurotoxicity and neurodegeneration in striatal cells via altered metal transport and protein kinase C delta dependent oxidative stress and apoptosis signaling mechanisms

Simplified cartoon of the hypothesized relationship between heterozygous HTT and Cd(II) exposure in a striatal cell. Cd(II) exposure and heterozygous HTT cooperatively activate NOX-mediated oxidative stress pathways resulting in altered antioxidant buffering capacity and increased caspase 9 and caspase 3 as well as PKCδ activation while blocking the activation of ERK and reducing DMT1 protein expression. All these events lead to neurotoxicity and neurodegeneration in the HD striatal cells. Pre-treatment with exogenous antioxidants, Zn(II), Mn(II) and Fe(II), as well as apocynin significantly attenuates Cd(II)-induced neurotoxicity in the heterozygous HTT cells compared to wild-type cells. [Display omitted] •Heterozygous huntingtin (HTT) enhances cadmium (Cd)-induced neurotoxicity and neurodegeneration in striatal cells.•Heterozygous HTT expressing striatal cells exhibit neurotoxic properties upon Cd exposure to cause cell death via caspase mediated apoptosis.•Expression of HTT increases accumulation of Cd and modulates ERK and PKCδ dependent oxidative signaling mechanisms upon Cd exposure.•Treatment with exogenous antioxidants and heavy metals significantly attenuate Cd-induced cytotoxicity in heterozygous HTT striatal cells. Huntington’s disease (HD) is functionally linked to environmental factors including cigarette use and dyshomeostasis in the levels of metals. Interestingly, one of the most abundant heavy metals in cigarettes is cadmium (Cd), which also accumulates in the striatum and causes neurotoxicity upon exposure. Thus, we hypothesized that heterozygous huntingtin (HTT), responsible for the majority of cases of HD in patients, in combination with Cd exposure would cause neurotoxicity and neurodegeneration via increased intracellular accumulation of Cd and activation of oxidative stress signaling mechanisms in a mouse striatal cell line model of HD. We report that heterozygous HTT striatal cells are significantly more susceptible to Cd-induced cytotoxicity as compared to wild-type HTT cells upon exposure for 48 h. The heterozygous HTT and Cd-induced cytotoxicity led to a NADPH oxidase (NOX) mediated oxidative stress that was attenuated by exogenous antioxidants and a NOX inhibitor, apocynin. Heterozygous HTT coupled with Cd exposure caused increased expression of protein kinase C δ (PKCδ) and other key oxidative stress proteins levels, enhanced the activation of caspase-9 and caspase-3 mediated apoptosis, and blocked the overexpression of extrace