The role of calcium‐binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis

Abstract

The factors contributing to selective motoneuron loss in amyotrophic lateral sclerosis (ALS) remain undefined. To investigate whether calcium-binding proteins contribute to selective motoneuron vulnerability in ALS, we compared calbindin-D28K and parvalbumin immunoreactivity in motoneuron populations in human ALS, and in a ventral spinal cord hybrid cell line selectively vulnerable to the cytotoxic effects of ALS IgG. In human autopsy specimens, immunoreactive calbindin-D28k and parvalbumin were absent in motoneuron populations lost early in ALS (i.e., cortical and spinal motoneurons, lower cranial nerve motoneurons), while motoneurons damaged late or infrequently in the disease (i.e., Onuf's nucleus motoneurons, oculomotor, trochlear, and abducens nerve neurons) expressed markedly higher levels of immunoreactive calbindin-D28K and/or parvalbumin. Motoneuron-neuroblastoma VSC 4.1 hybrid cells lost immunoreactive calbindin-D28k and parvalbumin following dibutyryl-cyclic AMP-induced differentiation and were killed by IgG from ALS patients. Undifferentiated calbindin/parvalbumin-reactive VSC 4.1 cells were not killed, nor were other cell lines expressing high levels of calbindin-D28K and parvalbumin immunoreactivity (substantia nigra-neuroblastoma hybrid cells and N18TG2 neuroblastoma parent cells). These studies suggest that decreased calbindin-D28K and parvalbumin immunoreactivity may help explain the selective vulnerability of motoneurons in ALS.

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…It has been extensively described that calcium dysregulation and excitotoxicity are 2 main pathogenic mechanisms of ALS pathology [45,46]. ALS-vulnerable spinal and brainstem MNs display low endogenous Ca 2+ buffering capacity, that is 5 to 6 times lower than that found in ALSresistant MNs (i.e., oculomotor MNs), making them more susceptible to excitotoxic insults [47]. NMDA receptor is considered to be 1 of the key elements in excitotoxiciy [46].…”

Focal degeneration of astrocytes in amyotrophic lateral sclerosis

“…3,4,13 Motor cells are potentially highly vulnerable to changes in extracellular glutamate levels as they express a large number of calcium-permeable AMPA receptors 12,[31][32][33] and have limited capacity to buffer calcium. 34 Although astrocytes express functional glutamate receptors, they are normally more resistant to stimuli that are excitotoxic for neurons. However, in this study, we found that cultured astrocytes that express hSOD1 G93A or hSOD1 G85R become susceptible to concentrations of exogenous glutamate that are not detrimental for wild-type astrocytes.…”

Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

“…All above commented data are consistent with the possibility that hippocampal neuronal death is mediated by TMTinduced intracellular Ca 2+ overload activating apoptotic pathways. The hypothesis that Ca 2+ -binding proteins such as CR which play a protective role against cell-deathinducing Ca 2+ overload has also been advanced in a series of neuropathological conditions including amyotrophic lateral sclerosis, ischaemia, AD and Parkinson's disease (Alexianu et al 1994;Mouatt-Prigent et al 1994;Yenari et al 2001;Attems et al 2008;Mattson 2007), and in experimental models of brain injury (Isaacs et al 1997;Dekkers et al 2004;Sasaki et al 2006), although this hypothesis has not been conclusively demonstrated. It is noteworthy in this respect that in the present experimental conditions CR-containing cells do not show signs of early commitment to death as indicated by experiments of doublelabelling for CR and annexin V.…”