p53 and Cell Cycle Proteins Participate in Spinal Motor Neuron Cell Death in ALS~!2010-02-16~!2010-02-19~!2010-04-14~!

Abstract

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 of hyperphosphorylated retinoblastoma (ppRb) and E2F-1 in ALS spinal cord motor neurons. In this study we examined the levels of the cell cycle checkpoint tumor suppressor protein p53 with concurrent changes in cell death markers during ALS. Expression and subcellular distribution of p53, retinoblastoma, Bax, Fas, and caspases were explored by immunoblot, immunohistochemistry and double-label confocal microscopy in the spinal cord and motor cortex of ALS and control subjects. We identified elevated levels of p53 in ALS spinal cord motor neurons but not neurons in the motor cortex. In addition, there was an increase in Bax, Fas, caspases-8 and -3 proteins in ALS spinal motor neurons. While caspase-3 and TUNEL labeled neurons were positive for ppRb, E2F-1 and p53 in spinal motor neurons, and Fas co-localized with caspase-8 in spinal motor neurons, we failed to observe these results in large neurons in the motor cortex of ALS subjects. We have linked p53 and activation of G1 to S phase cell cycle regulators to an apoptotic mode of cell death ALS spinal cord motor neurons.

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Morphometric analysis of our in vitro ALS model revealed a reduction in the soma size, maximum neurite length, as well as average neurite tree length in mutant MNs at day 44 compared with the control MNs, while genetic correction of the mutation improved these morphological characteristics in the isogenic MNs (Figures 2E–2G). We also observed significantly higher levels of the tumor suppressor p53 (TP53) in the nuclei of mutant SOD1 MNs compared with both the healthy control and isogenic MNs (Figure 2H), which is concordant with activated p53 observed in ALS postmortem spinal tissue as well as rodent models of ALS (Qiu et al., 2014, Ranganathan and Bowser, 2010). Studies on the SOD1 G93A mouse model of ALS, as well as a recent iPSC model of SOD1 ALS, have revealed heightened endoplasmic reticulum (ER) stress in ALS MNs (Kiskinis et al., 2014, Nishitoh et al., 2008).…”

MiR-375 is Essential for Human Spinal Motor Neuron Development and May Be Involved in Motor Neuron Degeneration

“…TP53 mediated apoptosis has been implicated in neuronal degeneration in Parkinson's disease as well as amyotrophic lateral sclerosis (ALS) where spinal motor neurons from ALS patients have been shown to display higher levels of p53 protein . A role for p53‐mediated apoptosis has also been suggested in the neuronal degeneration observed in spinal muscular atrophy (SMA).…”

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…Although best known as a tumor suppressor induced by DNA damage, several studies have documented p53 induction in patient tissue and in experimental models of a variety of chronic and acute neurodegenerative disorders (Culmsee and Mattson, 2005), which include Alzheimer's disease (de la Monte et al, 1997; Kitamura et al, 1997), Huntington’s disease (Bae et al, 2005), Parkinson's disease (Duan et al, 2002; Mogi et al, 2007; Qi et al, 2016), ALS (Martin, 2000; Ranganathan and Bowser, 2010) and traumatic brain injury (Yang et al, 2016). Interestingly, our results demonstrate that induction and nuclear accumulation of p53 are not sufficient to drive neurodegeneration in vivo .…”