Calbindin‐D_28Kis increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons

Abstract

Slow glutamate-mediated neuronal degeneration is implicated in the pathophysiology of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The calcium-binding proteins calbindin-D28K and parvalbumin have been reported to protect neurons against excitotoxic insults. Expression of calbindin-D28K is low in adult human motor neurons, and vulnerable motor neurons additionally may lack parvalbumin. Thus, it has been speculated that the lack of calcium-binding proteins may, in part, be responsible for early degeneration of the population of motor neurons most vulnerable in ALS. Using a rat organotypic spinal cord slice system, we examined whether the most potent neuroprotective factors for motor neurons can increase the expression of calbindin-D28K or parvalbumin proteins in the postnatal spinal cord. After 4 weeks of incubation of spinal cord slices with 1) glial cell line-derived neurotrophic factor (GDNF), 2) neurturin, 3) insulin-like growth factor I (IGF-I), or 4) pigment epithelium-derived factor (PEDF), the number of calbindin-D28K -immunopositive large neurons (>20 μm) in the ventral horn was higher under the first three conditions, but not after PEDF, compared with untreated controls. Under the same conditions, parvalbumin was not upregulated by any neuroprotective factor. The same calbindin increase was true of IGF-I and GDNF in a parallel glutamate toxicity model of motor neuron degeneration. Taken together with our previous reports from the same model, which showed that all these neurotrophic factors can potently protect motor neurons from slow glutamate injury, the data here suggest that upregulation of calbindin-D28K by some of these factors may be one mechanism by which motor neurons can be protected from glutamate-induced, calcium-mediated excitotoxicity.

Single-cell transcriptomic analysis unveils spinal motor neuron subtype diversity underpinning the water-to-land transition in vertebrates

“…We have defined these two new types of neurons as MNs based on the facts that: (1) they co-express MN hallmark genes Mnx1, Chat, and Slc18a3 (VAChT); and (2) both types extend their axons from the spinal cord to peripherals. Although Calb1 is a salient marker for V1 subtype Renshaw cells 86 , the presence of a small number of Calb1 + MNs among adult spinal MNs has been reported previously 87,88 . In those studies, it was hypothesized that MNs are protected from glutamate-induced and calcium-mediated excitotoxicity via increased Calb1 expression.…”

Specific vulnerability of iPSC-derived motor neurons with TDP-43 gene mutation to oxidative stress

“…Previous reports have suggested that motor neurons are vulnerable in ALS because they are larger than other cells; require large amounts of energy to maintain homeostatic ionic gradients and generate action potentials; are easily overloaded [ 36 ]; and have a lower buffering capacity for glutamate-triggered calcium ion influx [ 37 ], decreased expression of calcium-binding proteins such as CalbindinD28K and parvalbumin [ 38 , 39 ], and decreased expression of GABAA receptor α1, which is involved in inhibitory synaptic transmission [ 40 , 41 ]. TDP-43 mislocalization from the nucleus to the cytoplasm is more common in neurons than in other cells in ALS [ 42 ], and the half-life of mutant TDP-43 is longer than that of WT TDP-43 [ 5 ], suggesting that alterations in TDP-43 function may enhance motor neuron vulnerability in ALS.…”

The neuropathological investigation of the brain in a monkey model of autism spectrum disorder with ABCA13 deletion

“…In the present study, the intensive CaBp immunoreactivity was identified in the frontal cortex, but PV and/or NPY, other GABAergic makers, immunoreactivity would be weak on the contrary. CaBp is a marker of GABAergic neurons; however, this protein also has a neuroprotective function against neurodegeneration and ischemia (Greene et al, 2001; Iritani et al, 2001; Freimann et al, 2010; Spruill and Kuncl, 2015). In case of there being an ABCA13 deficit in the cortex, the neurons might induce neuroprotective mediators.…”