S100A6, a calcium- and zinc-binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by selective degeneration of motoneurones. Familial ALS is an age-dependent autosomal dominant disorder in which mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1) is linked to the disease. An animal model for this disease is a transgenic mouse expressing the mutated human SOD1(G93A) gene. Recent electrophysiological data emphasised that the striking selective vulnerability of motoneurones might be due to their differential calcium buffering capacities. Therefore we have investigated, using immunohistochemistry, the expression of different calcium binding proteins in brainstem and spinal cord from normal and SOD1 mutated mice. Among the 13 calcium-binding proteins screened, only one, S100A6, a homodimeric calcium-binding protein able to bind four Zn(2+), appeared to be highly expressed in the SOD1 mutated mice. In brainstem, reactive astrocytes, but not motoneurones, from several regions, including nerve 12 root, were highly S100A6-positive. Hypoglossal nucleus was negative for S100A6. In dorsal root, reactive astrocytes from both white matter and anterior horn were highly reactive. If overexpression of S100A6 is specific for ALS, it will be a valuable diagnostic marker for this disease.

S100B and S100A6 Differentially Modulate Cell Survival by Interacting with Distinct RAGE (Receptor for Advanced Glycation End Products) Immunoglobulin Domains

“…It appears that the RAGE/S100 system is highly adaptive and enables brain cells to respond in an appropriate manner to changes in the extracellular environment. The modulation of the expression of RAGE and S100 proteins during pathological states could alter this regulatory balance and would then lead to cellular dysfunctions (23,37,56,57). However, these findings raise the question of the functional relevance of micromolar concentration of S100B and S100A6 in the brain in vivo.…”

Cu/Zn Superoxide Dismutase Typical for Familial Amyotrophic Lateral Sclerosis Increases the Vulnerability of Mitochondria and Perturbs Ca2+Homeostasis in SOD1G93AMice

“…PCR genotyping procedure was adapted from Hoyaux et al (2000). The Tg male mice were bred with female B6SJL F1-hybrids obtained from The Jackson Laboratory and from Charles River Laboratories (Sulzfeld, Germany).…”

S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) Aggregation

“…Whereas Waltz relies on a combination of amyloid-prone sequence pattern recognition based on physicochemical properties and homology modeling, Zyggregator correlates sequence information with experimental aggregation rate changes upon mutation and polypeptide physicochemical properties. Both algorithms predict significant aggregation prone regions in helices H I (residues [11][12][13][14][15][16][17][18] and H IV (residues 71-82), within the hydrophobic core of S100A6 ( Fig. 1).…”

“…In turn, these ALS-affected neurons contain cytoplasmic aggregates of Cu/Zn Superoxide Dismutase (SOD1), which are ubiquitous disease indicators (16). For this reason, S100A6 has been proposed as a marker for ALS (17). Also, in AD, S100A6 is up-regulated in the brain white matter as well as in gray matter astrocytes surrounding the A␤ senile plaques, both in human patients and mouse models (10).…”