Lack of a functional MeCP2 protein leads to Rett syndrome by altering levels of brain proteins associated with energy metabolism and protein regulation, a study in a mouse model suggests.
These altered protein levels might also predict Rett syndrome’s progression, the investigators said.
The study, “Brain protein changes in Mecp2 mouse mutant models: Effects on disease progression of Mecp2 brain specific gene reactivation,” was published in the Journal of Proteomics.
Rett syndrome is caused by mutations in the MECP2 gene that result in a missing functional MeCP2 protein, a regulator of gene expression. Despite prior studies in animal models, little research has focused on the effects of MeCP2 deficiency in the levels of other proteins in the brain, as well as in Rett syndrome’s progression.
Researchers from Italy used a mouse model of Rett to address this gap. They did a proteomic analysis of the brains of mice both before and after they developed symptoms, and compared the data to controls without MECP2 mutations. (Proteomics is the large-scale study of proteins, conducted to draw more global conclusions than possible if assessing proteins one-by-one.)
Results showed abnormal levels of 20 brain proteins in symptomatic mice with Rett syndrome. Twelve of these proteins were overproduced, while eight were at lower levels compared to non-diseased control mice.
Notably, eight (40%) of these 20 proteins were involved in energy metabolism (the process by which cells get energy), and six (30%) were involved in proteostasis, which refers to cellular processes to ensure proper production and folding of proteins.
Presymptomatic mice showed abnormal levels in 18 proteins; 10 at low levels and 8 at high levels compared to controls. Similar to symptomatic mice, these proteins were primarily involved in energy metabolism and proteostasis.
The team then looked at mice that had been engineered to turn the MECP2 gene “on” in the brain, which was associated with mild symptoms and a longer life than otherwise expected.
By comparing animals lacking functional MeCP2 to mice with so-called MECP2 gene reactivation, the researchers worked to identify the proteins most directly impacted by missing MeCP2.
They found 12 proteins whose levels were normalized by gene reactivation. Seven of these proteins were at low levels and five at high levels without functional MeCP2 protein. Again, most were associated with energy metabolism and proteostasis, while two proteins were involved in how cells respond to oxidants — reactive molecules that can damage DNA and cellular structures — that is called redox regulation.
Only two of these 12 proteins, PYL2 and SODC, had been previously associated with Rett syndrome via earlier animal model studies that recorded altered levels in the brain.
“Our findings suggest that RTT [Rett syndrome] is characterized by a complex metabolic dysfunction strictly related to energy metabolism, proteostasis processes pathways and redox regulation mechanisms,” the researchers wrote.
“Alteration in the evidenced cellular processes, brain pathways and molecular mechanisms … [suggest] the possibility of the use of proteins as predictive biomarkers,” they added.
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