Longitudinal assessment of metal concentrations and copper isotope ratios in the G93A SOD1 mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, which involves progressive motor neuron degeneration in the central nervous system (CNS). The G93A SOD1 mouse model simulates one of the most common causes of familial ALS through the overexpression of a mutated form of the human gene encoding copper/zinc superoxide dismutase (SOD1). Transition metals, particularly Cu and Zn, have been shown to behave abnormally in the disease context and have been hypothesized to contribute to and potentially trigger the disease. In this study, concentrations of Cu, Zn and Fe, as well as Cu isotope ratios were assessed in keystone tissues of ALS, including the brain, spinal cord, muscle and whole blood, from transgenic mutant SOD1 mice and non-transgenic controls. While no consistent Cu isotope signal was found to be related to the disease state, concentrations of Cu, Zn and Fe were significantly elevated in muscle tissue of the transgenic mice, even at pre-symptomatic time points. In brain and muscle tissue, in both animal groups, a time-dependent Cu isotope signal was observed. We hypothesize that the early and significant elevation in metal concentration in muscle tissue from SOD1 transgenic mice could facilitate the development of ALS, without affecting the overall signal from well-buffered CNS tissues. Ageing may be recorded isotopically as a shift from a neonatal Cu pool as inherited from the mother, through dietary Cu and recycling processes.

Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis

“…In relation to this, alterations in copper influx/efflux have been evidenced in the SOD1-G93A mice. In particular, elevated concentrations of copper in this mutant SOD1 model have been reported early at pre-symptomatic phases within the SC and skeletal muscles, and this condition aggravates as disease progresses (Refs 60, 61), suggesting that copper dyshomeostasis might facilitate the development of ALS. Further, studies in mice with genetic modifications in copper-handling enzymes have confirmed the putative role of copper homeostasis in SOD1 toxicity.…”

Inter-comparison of stable iron, copper and zinc isotopic compositions in six reference materials of biological origin

“…The blood Cu isotopic composition has been shown to become lighter during ageing in a remote human Yakut population [25], and experiments on ageing C. elegans have confirmed this finding [26]. Copper isotopic compositions are highly sensible to disease conditions and have been investigated as a new biomarker for Wilson disease [27,28], cancer [29,30], liver diseases [24,31] and neurodegenerative disorders [32][33][34][35].…”

Assessment of metal concentrations in the SOD1G93A mouse model of amyotrophic lateral sclerosis and its potential role in muscular denervation, with particular focus on muscle tissue

“…indicate accumulation of Cu in the spinal cord (Li et al, 2006;Tokuda et al, 2015Tokuda et al, , 2014Tokuda et al, , 2013Tokuda et al, , 2008 at single time points, as well as over time (Tokuda et al, 2009(Tokuda et al, , 2007. Brain tissue showed a similarly varied behavior with studies reporting both elevated concentrations (Hilton et al, 2016), or no change to healthy controls (Enge et al, 2017;Lelie et al, 2011;Li et al, 2006;Tokuda et al, 2009Tokuda et al, , 2007. These changes in Cu and Zn concentrations have been postulated to play an important role in the toxic-gain-of-function associated with mSOD1 (Borchelt et al, 1994;Hilton et al, 2015).…”

“…While the accumulation and/or depletion of metals in different tissues reported in the literature are inconsistent, overall there appears to be accumulation in tissues of diseased mice. Tissues associated with the autonomic nervous system (ANS) have been shown to accumulate Cu and Zn (Enge et al, 2017;Hilton et al, 2016), with muscle tissue demonstrating pre-symptomatic increases in concentrations (Enge et al, 2017). Results from central nervous system (CNS) tissues…”