Parvalbumin and calbindin D‐28k in the human motor system and in motor neuron disease

Abstract

Calbindin D-28k and parvalbumin are neuronal calcium binding proteins of interest in relation to neurodegenerative diseases. Expression of calbindin and parvalbumin may be one of the determinants of selective vulnerability in these disorders. The distribution of these proteins was surveyed in the normal human motor system and in motor neuron disease (MND) using immunocytochemistry in formalin fixed post-mortem tissues. CNS tissues from 14 MND patients (mean age 61.2 years, mean post-mortem delay 24.6 h) and seven controls (mean age 62.6 years, mean post-mortem delay 25.3 h) were studied. Preliminary studies on the effects of fixation were performed. In normal cases upper and lower motor neurons showed absent expression of both proteins. Several neuronal groups characteristically spared in MND showed varying patterns of immunoreactivity: oculomotor neurons showed parvalbumin staining of the perikaryon; the thoracic preganglionic sympathetic neurons showed calbindin staining in perikarya. Onuf's nucleus showed calbindin staining in the neuropil only. In motor neuron disease a loss of ventral horn interneurons and calbindin immunoreactive processes was observed with no other disease related changes in the spinal cord, brain-stem, or motor cortex. These findings are consistent with the hypothesis that the distribution of these proteins is one determinant of selective vulnerability to the neurodegenerative processes in MND acting via disturbance of neuronal calcium homeostasis.

Expression of calbindin-D28K in motoneuron hybrid cells after retroviral infection with calbindin-D28K cDNA prevents amyotrophic lateral sclerosis IgG-mediated cytotoxicity.

“…The data obtained with our motoneuron cell line correlate well with the findings in human central nervous system where motoneurons that degenerate early in ALS have no calbindin-D28K and/or parvalbumin expression whereas motoneurons that are infrequently or only very late affected have significant immunoreactivity for these calcium-binding proteins (6,7). The importance of calcium homeostasis in the pathogenesis of motoneuron injury in ALS is supported by the in vivo passive transfer experiments (29), which document that injection of ALS immunoglobulins induces an increase in synaptic vesicles at motor end plates and in terminals synapsing on motoneuron perikarya as well as an increase in calcium-containing precipitates in synaptic terminals and in the cell body of motoneurons that lack calcium-binding proteins.…”

“…Calbindin-D28K and/or parvalbumin have been implicated in ALS pathogenesis since immunoreactivity for these calcium binding proteins is absent in neurons early and severely affected in ALS such as ventral horn motoneurons and is present in neurons late or infrequently affected such as oculomotor neurons or Onufs neurons (6,7). In addition, motoneuron hybrid cells that are selectively killed by ALS IgG have little or absent immunoreactivity for calbindin-D28K and parvalbumin whereas cells not affected by ALS IgG, including undifferentiated motoneuron hybrid cells and the parent neuroblastoma N18TG2 cells, have high levels of calbindin-D28K and parvalbumin (7).…”

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

“…Notably, motor neurons in the nuclei of oculomotor nerves are also much less vulnerable in ALS patients; this has been attributed to differential expression levels of Ca 2ϩ -binding proteins, particularly parvalbumin, among motor neurons in different cranial nerve nuclei. Expression of parvalbumin is high in oculomotor neurons and low in the facial and spinal motor neurons (Ince et al, 1993). Indeed, overexpression of parvalbumin attenuated kainateinduced Ca 2ϩ transients and protected spinal motor neurons from resultant neurotoxicity in parvalbumin transgenic mice (Van Den Bosch et al, 2002).…”

CytochromecAssociation with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice

“…Abnormalities of the glutamate transporter EAAT2 (excitatory amino acid transporter 2) can increase postsynaptic glutamate concentrations (Lin et al, 1998;Heath and Shaw, 2002), providing such a stress. In addition, motor neurons lack important Ca 2ϩ buffering proteins such as parvalbumin and calbindin D28K (Ince et al, 1993).…”