Modest Static Pressure Can Cause Enteric Nerve Degeneration Through Ectodomain Shedding of Cell Adhesion Molecule 1

Internal pressure is often involved in neurodegeneration; intraocular and intraventricular pressure elevations over 20-30 cmH₂O cause glaucoma and hydrocephalus, respectively. Here, we investigated enteric nerve degeneration in colon segments having tumor-induced stenosis and dilation and examined the mechanism of intraluminal pressure involvement. Histological examination revealed that the enteric ganglion neurons and neurites decreased in density in the dilated colons proportionate to the degree of dilation. Western blot analysis for cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member expressed in enteric neurons, revealed that ectodomain shedding of CADM1 increased proportionate to colon dilation, with increased production of its C-terminal fragment αCTF, a proapoptotic intracellular molecule. To link these neurodegenerative events to increased intraluminal pressure, we devised a two-chamber culture system wherein cells cultured on a semipermeable membrane were subjected to increased medium height (water pressure up to 50 cmH₂O). Mouse dorsal root ganglion (DRG) neurons were examined for expansion of their neurite networks in this system. As the pressure increased to 15, 30, and 45 cmH₂O, the neurites decreased in density and became thinner. In addition, CADM1 shedding increased with more αCTF production. CADM1 immunofluorescence and Mitotracker mitochondrial labeling revealed that as the pressure increased, neuritic CADM1 distribution changed from uniform to punctate staining patterns, and neuritic mitochondria decreased in number and appeared as course particles. These pressure-induced phenotypes were reproduced by exogenous expression of αCTF in standard DRG neuron cultures. Therefore, increases in colonic intraluminal pressure might cause enteric nerve degeneration by inducing CADM1 shedding and αCTF production.