Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice

Kieran, D; Woods, I; Villunger, A; Strasser, A; Prehn, JHM

Author(s): Kieran, D; Woods, I; Villunger, A; Strasser, A; Prehn, JHM;
Details: Publication Year 2007-12-18,Volume 104,Issue #51,Page 20606-20611
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
Abstract: BH3-only proteins couple diverse stress signals to the evolutionarily conserved mitochondrial apoptosis pathway. Previously, we reported that the activation of the BH3-only protein p53-up-regulated mediator of apoptosis (Puma) was necessary and sufficient for endoplasmic reticulum (ER) stress- and proteasome inhibition-induced apoptosis in neuroblastoma and other cancer cells. Defects in protein quality control have also been suggested to be a key event in ALS, a fatal neurodegenerative condition characterized by motoneuron degeneration. Using the SOD1(G93A) mouse model as well as human post mortem samples from ALS patients, we show evidence for increased ER stress and defects in protein degradation in motoneurons during disease progression. Before symptom onset, we detected a significant up-regulation of Puma in motoneurons of SOD1(G93A) mice. Genetic deletion of puma significantly improved motoneuron survival and delayed disease onset and motor dysfunction in SODJG93A mice. However, it had no significant effect on lifespan, suggesting that other ER stress-related cell-death proteins or other factors, such as excitotoxicity, necrosis, or inflammatory injury, may contribute at later disease stages. Indeed, further experiments using cultured motoneurons revealed that genetic deletion of puma protected motoneurons against ER stress-induced apoptosis but showed no effect against excitotoxic injury. These findings demonstrate that a single BH3-only protein, the ER stress-associated protein Puma, plays an important role during the early stages of chronic neurodegeneration in vivo.
Publisher: NATL ACAD SCIENCES
Keywords: AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOPLASMIC-RETICULUM STRESS; TRANSGENIC MOUSE MODEL; CENTRAL-NERVOUS-SYSTEM; MOTOR-NEURON DEATH; CELL-DEATH; SUPEROXIDE DISMUTASE-1; CANCER-CELLS; ACTIVATION; SOD1
Publisher's Version: https://doi.org/10.1073/pnas.0707906105
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2007-12-18 12:00:00