Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is characterized by the irreversible loss of corticospinal neurons and motor neurons. Recent studies has demonstrated an anti-inflammatory activity for the Peroxisome Proliferator-Activated Receptor (PPARs) agonists, which in ALS have been able to decrease the production of proinflammatory genes, including cytokines and chemokines. The comprehension of the molecular mechanisms that are responsible for their neuroprotective activity of PPARs could possibly lead to identify new targets for unprecedented therapeutic approaches. Using a PPRE-Luc; hSOD1-G93AALS transgenic mice we investigated the PPAR transcriptional activity over the course of ALS pathogenesis. The analysis of the enzymatic activity of luciferase in the spinal cord and the brain areas of PPRE-Luc; hSOD1-G93A mice showed an abrupt increase of PPAR activity at the end stage of the disease in the spinal cord, which was not shared by the peripheral organs. Furthermore, it was not dependent on the metabolic modifications induced from the starvation that the animals experienced during the last days of their life when they are almost completely paralyzed. Analysis of the nuclear translocation of PPARα, PPARβ/δ and PPARγ in the spinal cord of hSOD1-G93A mice with an ELISA-based Transcription Factor Assay showed that the overall nuclear presence of the different isoforms of PPARs did not change during the course of the disease. Our results indicate that the increase in PPAR activity at the end stage of the disease could represent a compensatory mechanism aimed at counteracting the intense neurodegenerative process which takes place at this time.