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

Abstract

The discovery that Rett syndrome is caused by mutations in the MECP2 gene has provided a major breakthrough in our understanding of the disorder. However, despite this, there is still limited understanding of the underlying pathophysiology of the disorder hampering the development of curative treatments. Over the years, a number of animal models have been developed contributing to our knowledge of the role of MECP2 in development and improving our understanding of how subtle expression levels affect brain morphology and function. Transcriptomic and proteomic studies of animal models are useful in identifying perturbations in functional pathways and providing avenues for novel areas of research into disease.This review focuses on published transcriptomic and proteomic studies of mouse models of Rett syndrome with the aim of providing a summary of all the studies, the reported dysregulated genes and functional pathways that are found to be perturbed.The 36 articles identified highlighted a number of dysfunctional pathways as well as perturbed biological networks and cellular functions including synaptic dysfunction and neuronal transmission, inflammation, and mitochondrial dysfunction. These data reveal biological insights that contribute to the disease process which may be targeted to investigate curative treatments.

Meta-Analysis Identifies Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

“…Through this meta-analysis four modules of genes that were significantly dysregulated in the RTT transcriptome relative to the controls was identified. The pathways that were enriched in each of the four modules were investigated and it was identified that the brown4 module was mostly enriched in pathways related to immunological aberrations, which is consistent with previously published studies in RTT including one of our own [28,29], [30]. Next, the magenta module was enriched for pathways mostly involving the metabolic system, which also aligns with previously reported literature [31,32] .…”

“…Mice harbouring mutations in the MECP2 gene are one of the most clinically relevant models for RTT as they recapitulate many of the features observed in RTT patients, such as seizures and motor and cognitive dysfunction, which has assisted in our understanding of the underlying pathophysiology [8]. However, despite the vast majority of RTT patients being female, most gene therapy and other preclinical studies in animal models of RTT have used male mice which is not truly representative of the patient population.…”

Proteomic profiling reveals mitochondrial alterations in Rett syndrome

“…In a previous study by Pecorelli et al [16], a microarray-based transcriptome-profiling revealed almost 500 differentially expressed genes in RTT PBMC, mainly upregulated transcripts related to key biological pathways such as mitochondrial function/organization and ubiquitination/proteasome system. While other transcriptomic investigations on RTT biological samples corroborated the microarray results, in particular regarding the atypical expression of mitochondrial-related genes [25], proteomics analyses are still quite limited in RTT [26][27][28][29][30]. Moreover, it is worth mentioning that a change in gene expression is not always associated with similar patterns in protein abundance.…”

Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders

“…The current list of RTT spectrum genes is especially enriched in chromatin modulators (such as HDAC1 , MEF2C , NCOR2, or SATB2 , and including MECP2 ) and genes involved in synaptic function (such as GABRB2, GRIN2B, SHANK3, IQSEC2, STXBP1, SLC6A1, or SYNGAP1 ) [ 11 , 62 ]. These pathways and functions have been found impaired in patients with RTT spectrum disorders, as well as in RTT animal models, and this might be the link between RTT spectrum genes and the reason why patients with RTT spectrum disorders present with overlapping features [ 72 , 73 ].…”