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Disturbances in Ca 2+  homeostasis and mitochondrial dysfunction have emerged as major pathogenic features in familial and sporadic forms of Amyotrophic Lateral Sclerosis (ALS), a fatal degenerative motor neuron disease. However, the distinct molecular ALS-pathology remains unclear. Recently, an activity-dependent Ca 2+  homeostasis deficit, selectively in highly vulnerable cholinergic motor neurons in the hypoglossal nucleus (hMNs) from a common ALS mouse model, the endstage superoxide dismutase SOD1 G93A  transgenic mouse, was described. This functional deficit was defined by a reduced hMN mitochondrial Ca 2+  uptake capacity and elevated Ca 2+  extrusion across the plasma membrane. To address the underlying molecular mechanisms, here we quantified mRNA-levels of respective potential mitochondrial and plasma membrane Ca 2+  transporters in individual, choline-acetyltransferase (ChAT) positive hMNs from wildtype (WT) and endstage SOD1 G93A  mice, by combining UV laser microdissection with RT-qPCR techniques, and specific data normalization. As ChAT cDNA levels as well as cDNA and genomic DNA levels of the mitochondrially encoded NADH dehydrogenase ND1 were not different between hMNs from WT and endstage SOD1 G93A  mice, these genes were used to normalize hMN-specific mRNA-levels of plasma membrane and mitochondrial Ca 2+  transporters, respectively. We detected about 2-fold higher levels of the mitochondrial Ca 2+  transporters MCU/MICU1, Letm1, and UCP2 in remaining hMNs from endstage SOD1 G93A  mice. These higher expression-levels of mitochondrial Ca 2+  transporters in individual hMNs were not associated with a respective increase in number of mitochondrial genomes, as evident from hMN specific ND1 DNA quantification. Normalized mRNA-levels for the plasma membrane Na + /Ca 2+  exchanger NCX1 were also about 2-fold higher in hMNs from SOD1 G93A  mice. Thus, pharmacological stimulation of Ca 2+  transporters in highly vulnerable hMNs might offer a neuroprotective strategy for ALS.

frontiers in cellular neuroscience

Elevated mRNA-levels of distinct mitochondrial and plasma membrane Ca2+ transporters in individual hypoglossal motor neurons of endstage SOD1 transgenic mice