Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome

Abstract

Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly impacting females. MECP2 is an epigenetic transcriptional regulator acting mainly to repress gene expression, though it plays multiple gene regulatory roles and has distinct molecular targets across different cell types and specific developmental stages. In this review, we summarize MECP2 loss-of-function associated transcriptome and proteome disruptions, delving deeper into the latter which have been comparatively severely understudied. These disruptions converge on multiple biochemical and cellular pathways, including those involved in synaptic function and neurodevelopment, NF-κB signaling and inflammation, and the vitamin D pathway. RTT is a complex neurological disorder characterized by myriad physiological disruptions, in both the central nervous system and peripheral systems. Thus, treating RTT will likely require a combinatorial approach, targeting multiple nodes within the interactomes of these cellular pathways. To this end, we discuss the use of dietary supplements and factors, namely, vitamin D and polyunsaturated fatty acids (PUFAs), as possible partial therapeutic agents given their demonstrated benefit in RTT and their ability to restore homeostasis to multiple disrupted cellular pathways simultaneously. Further unravelling the complex molecular alterations induced by MECP2 loss-of-function, and contextualizing them at the level of proteome homeostasis, will identify new therapeutic avenues for this complex disorder.

Keywords: Autism; Neurodevelopmental disorders; Neuroinflammation; Polyunsaturated fatty acids; Vitamin D.

Figure 1:. Extensive overlap of cellular pathways that are disrupted in the proteome of Rett syndrome models.

Reactome pathway analyses were performed on the proteins found to be dysregulated in multiple Rett syndrome studies. From the many pathways found to be dysregulated in two or more studies, many commonalities are observed when comparing studies performed on mouse Mecp2-mutant central nervous system tissues (Mouse CNS), RTT iPSC-derived neural progenitors and neurons (IPSC Neurons), and samples derived from RTT patients, which include plasma, saliva, and fibroblasts (Human Peripheral Samples). The overlapping pathways are listed in Table 2.

Figure 2:. Proposed mechanisms for rescue of disrupted proteome in Rett syndrome by Vitamin D and Polyunsaturated Fatty Acids (PUFAs).

MECP2 dysfunction is associated with increased (upward black arrow) or decreased (downward black arrow) expression of multiple proteins and cellular pathways in the central nervous system as well as peripheral organs and circulatory system (denoted by the term “periphery”) contributing to perturbations in physiological processes such as altered (up and down black arrows) neurodevelopment, and increased inflammation. These proteins include both direct targets of MECP2, and those that might be disrupted indirectly due to regulation by MECP2 targets (dashed arrows). Vitamin D and PUFAs have been shown to inhibit (red lines) or activate (blue arrows) several of these pathways in non-RTT studies, and to restore homeostasis to these pathways in RTT patients or Mecp2-mutant mouse models (weighted red lines and blue arrows). Vitamin D and PUFAs have tremendous potential to simultaneously rescue multiple disrupted pathways and provide a partial therapeutic for RTT.