Metformin Seen to Help Correct Defects in Neurons Lacking FMRP Protein
The common type 2 diabetes medication metformin eased the excessive production of proteins in nerve cells that were engineered in a lab to have the underlying defect seen in people with fragile X syndrome, a study reported.
These findings support further development of metformin as a treatment for fragile X, its researchers wrote, although “its therapeutic effects are likely to be partial.”
The study, “Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment,” was published in the journal Molecular Autism.
Fragile X, the most frequent genetic cause of autism, is characterized by a lack of FMRP, which controls the production of several other proteins in the brain. Understanding the precise effects of this protein’s absence on nerve cell biology is an ongoing area of study.
Previous research in mice indicated that FMRP’s lack leads to a global increase in protein synthesis in neurons. Other studies have shown increased protein production in skin cells from fragile X patients, but assessments in human neural cells — the cell types most relevant to manifestations of fragile X — are needed.
Metformin showed promise in early fragile X research, as it normalized protein synthesis and cell signaling in a mouse model of this disorder. Two patients, after one year of treatment with metformin, showed diminished cognitive and behavior problems.
Researchers in Singapore and Finland assessed protein synthesis and the effects of metformin working in neurons derived from human stem cells.
Using a battery of molecular biology tests, they first demonstrated that neurons genetically engineered to lack FMRP had increased expression of genes involved in protein production, at levels relative to neurons with a working FMRP protein.
Greater activity in two molecular pathways in FMRP-deficient nerve cells — MAPK/ERK1/2 and PI3K-Akt-mTOR — was indicated in subsequent experiments.
Researchers then found that meformin’s use on neurons lacking FMRP reduced this excess protein production, but no changes were seen in the activity of the Akt and ERK1/2 proteins.
“These results suggest that metformin’s effects on protein synthesis are, at least at the doses used here, independent of Akt/ERK1/2 pathway modulation,” the researchers wrote.
Cell lines used in fragile X studies are characterized by increased proliferation, which means dividing more frequently than normal, and poor growth of neurites — the projections that connect nerve cells to each other. Further experiments with metformin showed that normalizing protein synthesis in FMRP-deficient cells eased this excessive cell division, but did not restore neurite growth.
Notably, the highest metformin dose also significantly decreased cell division in neurons with functional FMRP, which is “consistent with the known properties of metformin and its effect on proliferation of various type of cells,” the scientists wrote.
“In this study, we demonstrate that global protein synthesis, a current target of therapeutic efforts, is elevated in FMRP-deficient human neural cells,” they concluded. “We further demonstrate that metformin, a candidate therapy presently in clinical trials, normalizes elevated protein synthesis and rescues some, but not all, neurodevelopmental abnormalities caused by FMRP deficiency in human neural cells.”