Phosphorylation of PPAR-gamma in ALS

Santarelli, Francesco

Abstract/Journal Article

DZNE-2020-00993

Phosphorylation of PPAR-gamma in ALS

Santarelli, F.DZNE*

2012

11th International Congress of Neuroimmunology, Boston, MA, USA, 4 Nov 2012 - 8 Nov 2012 Advances in neuroimmunology 253(1-2), 154 (2012)

Abstract: Objective: Oxidative stress, mitochondrial dysfunction and neuroin-flammation are pathological processes involved in amyotrophic lateralsclerosis (ALS), a neurodegenerative disorder characterized by a lossof upper and lower motor neurons. In animal models of neuro-degeneration several experiments using Thiazolidinediones (TZD),synthetic PPARγagonists, suggest a regulatory role of PPARγin inflam-matory pathways. However, clinical trials in ALS patients treated withagonists for PPARγhave failed. Thesefindings, together with the regu-lation of PPARγactivity mediated by post-translational modifications,brought us to study the specific inactivating phosphorylation site(Ser112/Ser82) of PPARγin human ALS tissue and in G93A SOD1mice, an animal model of ALS.Methods: G93A SOD1 mice from Jackson Laboratory were sacrificed at30, 60, 100 and 120 days of age. Cortex and spinal cord were analyzedin a total of 6 females and 3–6 males per age group. ALS and controlhuman spinal cord tissue was supplied by the Neurological TissueBank-University of Barcelona-Hospital Clínic-IDIBAPS.The phospho-PPARγprotein content was studied by western blot,quantified by Quantity One Analysis software (BioRad) and analyzedby GraphPad PrismR.Results:We found an age-dependent effect on phosphorylation ofPPARγin the spinal cord of mice, statistically significant in 100- and120-day-old G93A SOD1 mice.In human samples an increasing tendency of phosphorylatedPPARγprotein was observed between ALS and control cases.That tendency was clearer when tissue sample were sorted in thosefrom pure ALS and ALS with some other pathology (fronto-temporallobar degeneration or Alzheimer's disease related pathology).Conclusions:The increment of inactive phosphorylated PPARγlevels inthe spinal cord of the clinically affected mice (100- and 120-day-oldG93A SOD1), prompt a possible explanation for the inflammatory pro-cesses in the brain, one of the hallmarks of ALS and other neurodegen-erative disorders.The failure of clinical trials with PPARγagonist in ALS patientscould be explained by the increased levels of phosphorylated PPARγfound in the human samples.The levels of active/inactive PPARγseem to be important notonly with regard to the clinical presentation of the disease, butalso regarding to treatment efficiency. Understanding of thePPARγactivation/inactivation mechanisms will help in the devel-opment of new treatment regimens for ALS and other neurodegen-erative diseases.

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