Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome

• Published in: Journal of translational medicine 2023-10, Vol.21 (1), p.1-756, Article 756
• Main Authors: Musokhranova, Uliana, Grau, Cristina, Vergara, Cristina, Rodríguez-Pascau, Laura, Xiol, Clara, Castells, Alba A., Alcántara, Soledad, Rodríguez-Pombo, Pilar, Pizcueta, Pilar, Martinell, Marc, García-Cazorla, Angels, Oyarzábal, Alfonso
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Bioenergetics; Brain; Care and treatment; Cerebellum; Clinical trials; Convulsions & seizures; Diagnosis; Ethylenediaminetetraacetic acid; Exploratory behavior; Fibroblasts; Gene mutations; Genetic aspects; Genotype & phenotype; Health aspects; Homeostasis; Immunohistochemistry; Inflammation; Laboratories; Leriglitazone; MeCP2 protein; Medical treatment; Metabolic modulation; Methyl-CpG binding protein; Microscopy; Mitochondria; Neuroinflammation; Neuronal-glial interactions; Neurons; Neurophysiology; Neurotransmission; Oxidative stress; Pathophysiology; Phenotypes; Physiology, Pathological; Rett syndrome; Therapeutic applications; Type 2 diabetes; Ultrastructure; Weaning
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04622-5

Background Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment. Methods We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2.sup.tm1.1Bird-/+ mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPAR[gamma] agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel. Results We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity. Conclusions Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial. Keywords: Rett syndrome, Metabolic modulation, Bioenergetics, Neuroinflammation, Leriglitazone, Mitochondria