Lack of FMRP linked to inflammatory processes in brain in fragile X model
Altered levels of 100 proteins found with absence of FMRP in mouse study
The absence of fragile X mental retardation protein (FMRP) — absent or at low levels in people with fragile X syndrome — leads to protein changes linked to inflammatory processes in a brain region called the prefrontal cortex, according to a new study in mice.
In mice without FMRP, 100 proteins were found to have altered levels in the brain’s prefrontal cortex.
Among them were a subset involved in immune processes such as the complement and coagulation cascades. The complement cascade acts to boost the activity of antibodies and several immune cells.
“Given that [the] prefrontal cortex is a critical brain area for social interaction, the FMRP absence induced-changes of a subset of proteins might contribute to ASD [autism spectrum disorder]” in fragile X, the researchers wrote.
The study, “Proteome profiling of the prefrontal cortex of Fmr1 knockout mouse reveals enhancement of complement and coagulation cascades,” was published in the Journal of Proteomics.
Mouse model shows protein changes in brain
Fragile X is a main genetic cause of ASD and intellectual disability. The inherited disorder is caused by mutations in the FMR1 gene that result in low levels or a complete absence of the FMRP protein, which regulates the production of several other proteins involved in nerve cell communication.
Several studies have shown that FMRP controls the activity of many genes associated with brain development and other nerve cell processes, as well as ASD and intellectual disability.
While the prefrontal cortex has a crucial role in cognitive, emotional, motivational, and social behaviors, data on the effects of FMRP absence in protein composition of this region are lacking.
To fill this knowledge gap, a research team in China conducted a large-scale screening of the protein profile of the prefrontal cortex of healthy mice and mice lacking FMRP — a commonly used mouse model of fragile X.
Of the 5,851 proteins identified and quantified in the animals’ brain region, 100 showed significantly altered levels in the absence of FMRP. Specifically, 53 proteins had increased levels (upregulated) and 47 had decreased levels (downregulated).
Comparisons with previous studies assessing protein levels in other brain regions and tissues showed little overlap between proteins affected by the lack of FMRP. Only three of the 100 proteins in this study are encoded by genes previously identified as FMRP targets.
Importantly, a comparison with a database of human candidate genes for autism spectrum disorder showed that six of these 100 proteins were encoded by genes previously associated with ASD.
Although the different methods used in these studies may influence these comparisons, the findings suggest that FMRP absence causes “distinct protein profiles across different brain areas,” which “may provide new candidate genes for this disease,” the researchers wrote.
To investigate how these changes in protein levels might affect function, the research team used several software methods and tools. These were designed to assess links between proteins and a wide range of biological and cellular processes.
These bioinformatic analyses showed that proteins whose levels were significantly changed in the absence of FMRP were mainly involved in immune processes and oxygen-related mechanisms. Further, they were mostly located in the space outside cells, or the extracellular space.
Study: Loss of FMRP protein may lead to dysfunction
In particular, the complement and coagulation pathways were consistently found to be enriched in the absence of FMRP. Six upregulated proteins were involved in these cascades: FGA, FGB, and FGG in the coagulation cascade, and C3, C1QA, and SERPING1, in the complement pathways.
“The complement and coagulation cascades are critical for innate immune responses to extracellular stimuli and infection,” the researchers wrote. The innate immune system is the body’s first line of defense against viruses, infections, and other threats.
As such, these findings suggest “that loss of FMRP could lead to PFC [prefrontal cortex] dysfunction through dysregulation of immune system and extracellular stimuli,” they added.
Given that [the] prefrontal cortex is a critical brain area for social interaction, the FMRP absence induced-changes of a subset of proteins might contribute to ASD [autism spectrum disorder] in [fragile X].
Proteins whose levels were changed in the prefrontal cortex of FMRP-deficient mice also were involved in regulating nerve cell communication, fatty acids metabolism, and oxidative stress, “which might contribute to the PFC dysfunction upon loss of FMRP,” the team wrote.
Low levels of fatty acids, a type of fatty molecule, have been reported in fragile X patients, and oxidative stress is a type of cellular damage thought to contribute to nerve cell death in fragile X.
Further analysis of protein-protein interactions showed six interaction networks with 34 of the 100 proteins altered by loss of FMRP.
Five of the six proteins involved in the complement and coagulation cascades were present in the most complex network, while the sixth (C3) was present in a smaller network. This further indicates a crucial role of these proteins and the complement and coagulation cascades in the FMRP-lacking prefrontal cortex.
Taken together, these findings indicate “that the FMRP absence enhanced complement and coagulation cascades might be an important [disease-associated] causation of ASD in [fragile X] through dysregulation of innate immune system,” the research team wrote, noting that more studies are needed to confirm this hypothesis.