Quantitative proteomic alterations of human iPSC-based neuronal development indicate early onset of Rett syndrome

Abstract

Rett syndrome (RTT) is a progressive neurodevelopmental disease often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanisms by which impaired MeCP2 induces the pathological abnormalities in the brain are not understood. To understand the molecular mechanisms involved in disease, we used an RTT patient induced pluripotent stem cell (iPSC)-based model and applied an in-depth high-resolution quantitative mass spectrometry-based analysis during early stages of neuronal development. Our data provide evidence of proteomic alteration at developmental stages long before the phase that symptoms of RTT syndrome become apparent. Differences in expression profiles became more pronounced from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes and calcium signaling were already affected at initial stages. These results can help development of new biomarkers and therapeutic approaches by selectively target the affected proteins in RTT syndrome.

Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders

“…Further investigation using SILAC revealed that NPCs lacking MECP2 have increased expression of LIN28, which is known to repress differentiation into glial cells [130]. A recent study using iPSC neuron of Rett syndrome patients identified 4 subsets of proteins that were differentially expressed, across time points involved in filipodia assembly, synapses, axon guidance, and cytoskeleton and translation [131]. This showed distinct temporal deficits during neuronal development, highlighting the fluid pathology underlying Rett syndrome.…”