Persistent Unresolved Inflammation in theMecp2-308 Female Mutated Mouse Model of Rett Syndrome

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

Comprehensive Analysis of GABAA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease

“…These results are in agreement with the dataset reported by Renthal et al [38]. An increasing body of evidence pointing towards the importance of early intervention has been reported in the last few years, as reviewed by Constentino et al [39], and has extended from neurotransmission to other therapeutic targets in Rett syndrome, such as energetic dysfunction, as very recently published [40], or inflammatory processes [41,42].…”

Genome‐wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signaling pathways and cellular functions as potential therapeutic targets

“…The study by Matarazzo and Ronnett (), who studied protein expression in male Mecp2 ‐null mice at 2 weeks and 4 weeks of age, also revealed aberrant protein expression enriched in cytoskeletal arrangement as well as in other biological functional networks such as chromatin modeling, energy metabolism, cell signaling, and neuroprotection. In support of the transcriptomic studies, evidence of inflammation was observed by Cortelazzo et al (), who demonstrated differentially expressed proteins involved in the acute phase response and inflammation in the plasma of symptomatic Mecp2 –308 female mice (Cortelazzo et al, ).…”

“…The proteomic studies identified were conducted on three different Mecp2 mouse models: Mecp2 ‐null, Mecp2 308 , and Mecp2 Jae mice (Cortelazzo et al, ; Matarazzo & Ronnett, ; Pacheco et al, ). The ages of mice ranged from 2 weeks to 12‐months old.…”

“…The ages of mice ranged from 2 weeks to 12‐months old. Two studies were conducted on male mice (Matarazzo & Ronnett, ; Pacheco et al, ) with one study on female mice (Cortelazzo et al, ). Two studies were conducted on brain regions (Matarazzo & Ronnett, ; Pacheco et al, ) and one on plasma (Cortelazzo et al, ).…”

“…The three proteomic studies used slightly different protein analysis and quantification methods, with Matarazzo and Ronnett () using 2D gel electrophoresis and Q‐T of mass spectrometry. Cortelazzo et al () used 2D and MALDI‐ToF/ToF, while Pacheco et al () used an in‐gel tryptic digest and LC‐MS/MS.…”