Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R superoxide dismutase transgenic mice

In recent years, several mouse models of amyotrophic lateral sclerosis (ALS ) have been developed. One, caused by a G86R mutation in the superoxide dis mutase-1 (SOD-1) gene associated with familial ALS, has been subjected to e xtensive quantitative analyses in the spinal cord. However, the human form of ALS includes pathology elsewhere in the nervous system. In the present s tudy, analyses were extended to three motor nuclei in the brainstem. Mutant mice and control littermates were evaluated daily and mutants, along with their littermate controls, were killed when they were severely affected. Br ains were removed after perfusion and processed for Nissl staining, the sam ples were randomized, and the investigators were blinded to their genetic s tatus. Stereologic methods were used to estimate the number of neurons, mea n neuronal volumes, and nuclear volume in three brainstem motor nuclei know n to be differetially involved in the human form of the disease, the oculom otor, facial, and hypoglossal nuclei. In the facial nucleus, neuron number consistently declined (48%), an effect that was correlated with disease sev erity. The nuclear volume of the facial nucleus was smaller in the SOD-1 mu tant mice (45.7% difference from control mice) and correlated significantly with neuron number. The oculomotor and hypoglossal nuclei showed less extr eme involvement (<10% neuronal loss overall), with a trend toward fewer neu rons in the hypoglossal nucleus of animals with severe facial nucleus invol vement. In the oculomotor nucleus, neuronal loss was seen only once in five mice, associated with very severe disease. There was no significant change in the volume of individual neurons in any of these three nuclei in any tr ansgenic mouse. These results suggest that different brainstem motor nuclei are differentially affected in this SOD-1 mutant model of ALS. The relativ ely moderate and late involvement, of the hypoglossal nucleus indicates tha t, although the general patterns of neuronal pathology match closely those seen in ALS patients, some differences exist in this transgenic model compa red with the progression of the disease in humans. However, these patterns of cellular vulnerability may provide clues for understanding the different ial susceptibility of neural structures in ALS and other neurodegenerative diseases. J. Comp. Neurol. 416:112-125, 2000. (C) 2000 Wiley-Liss, Inc.