Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis type 8

Abstract

Amyotrophic Lateral Sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that Amyotrophic Lateral Sclerosis is part of a spectrum of disorders ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic Lateral Sclerosis type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localised to the cytoplasmic surface of the endoplasmic reticulum where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of Amyotrophic Lateral Sclerosis type 8 based on the VapBP56S mutation and VapB gene deletion have been generated in the rat. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of Amyotrophic Lateral Sclerosis type 8. A loss of motor neurones in VapBP56S/+ and VapBP56S/P56Sanimals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB-/-animals exhibit a relative increase in cytoplasmic TDP-43 levels compared to the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapBP56S/+, VapBP56S/P56S and VapB-/-animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extra motor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of Amyotrophic Lateral Sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.