p53 and Cell Cycle Proteins Participate in Spinal Motor Neuron Cell Death in ALS

摘要

Apoptosis has been implicated in many neurodegenerative diseases, including amyotrophic lateral sclerosis(ALS). We previously demonstrated a role for G1 to S phase cell cycle regulators in ALS with increased levels ofhyperphosphorylated retinoblastoma (ppRb) and E2F-1 in ALS spinal cord motor neurons. In this study we examined thelevels of the cell cycle checkpoint tumor suppressor protein p53 with concurrent changes in cell death markers duringALS. Expression and subcellular distribution of p53, retinoblastoma, Bax, Fas, and caspases were explored byimmunoblot, immunohistochemistry and double-label confocal microscopy in the spinal cord and motor cortex of ALSand control subjects. We identified elevated levels of p53 in ALS spinal cord motor neurons but not neurons in the motorcortex. In addition, there was an increase in Bax, Fas, caspases-8 and -3 proteins in ALS spinal motor neurons. Whilecaspase-3 and TUNEL labeled neurons were positive for ppRb, E2F-1 and p53 in spinal motor neurons, and Fas colocalizedwith caspase-8 in spinal motor neurons, we failed to observe these results in large neurons in the motor cortex ofALS subjects. We have linked p53 and activation of G1 to S phase cell cycle regulators to an apoptotic mode of cell deathALS spinal cord motor neurons.