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

TLDR

The factors contributing to selective motoneuron loss in amyotrophic lateral sclerosis remain undefined. The study compared calbindin‑D 28K and parvalbumin immunoreactivity in human ALS motoneurons and a ventral spinal cord hybrid cell line to assess their role in selective vulnerability. Human ALS autopsy samples showed that early‑lost motoneurons lacked calbindin‑D 28K and parvalbumin, whereas late‑lost or spared motoneurons expressed high levels, and differentiated VSC 4.1 hybrid cells that lost these proteins were vulnerable to ALS IgG while undifferentiated or other high‑protein cells were resistant, indicating that reduced calbindin‑D 28K and parvalbumin immunoreactivity may underlie selective motoneuron vulnerability.

Abstract

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‐D 28K 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‐D 28K 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‐D 28K and/or parvalbumin. Motoneuron–neuroblastoma VSC 4.1 hybrid cells lost immunoreactive calbindin‐D 28K 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‐D 28K and parvalbumin immunoreactivity (substantia nigra–neuroblastoma hybrid cells and N18TG2 neuroblastoma parent cells). These studies suggest that decreased calbindin‐D 28K and parvalbumin immunoreactivity may help explain the selective vulnerability of motoneurons in ALS.