title: Accumulation of labile zinc in neurons and astrocytes in the spinal cords of G93A SOD-1 transgenic mice.
abstract: Zinc dyshomeostasis may trigger oxidative stress, which is likely the key mechanism of neuronal death in amyotrophic lateral sclerosis (ALS), including familial forms such as G93A SOD-1 ALS. Since zinc binding by G93A SOD-1 is weaker than by normal SOD-1, we assessed whether labile zinc levels are altered in the spinal cords of G93A SOD-1 transgenic (Tg) mice. Whereas no zinc-containing cells were found in wild-type (WT) mice, neurons and astrocytes with high levels of labile zinc appeared in G93A SOD-1 Tg mice, in correlation with motoneuron degeneration. The level of HNE, an endogenous neurotoxic molecule, was increased around zinc-accumulating cells and mSOD-1 positive cells, suggesting a link between HNE, SOD-1 mutation and zinc accumulation. Moreover, exposure of cultured spinal neurons and astrocytes from G93A SOD-1 Tg mice to HNE increased labile zinc levels, and exposure to zinc increased 4-hydroxynonenal (HNE) levels, to a greater degree than in WT neurons and astrocytes. Administration of the zinc chelator TPEN extended survival in G93A SOD-1 Tg mice. These results indicate that zinc dyshomeostasis occurs in the spinal cords of Tg mice, and that this dyshomeostasis may contribute to motoneuron degeneration.
authors.affiliation: Univ. Ulsan Col. Med., Seoul, Republic of Korea.
authors.forename: Jean
authors.initials: J
authors.lastname: Kim
authors.forename: Tae-Youn
authors.initials: TY
authors.lastname: Kim
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Gwag
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh