Talk Presented by: Dr. Nisha Raj, the PI of the Karim’s lab
Summarized by: Andrew Gaulden, Postdoctoral Researcher, Cincinnati Children’s Hospital Medical Center
Summary
Dr. Nisha Raj lab in Emory studied the difference in RNA and Protein levels in FXS and FXTAS patients’ brain. Transcription is the process where a cell makes an RNA copy of a gene’s instructions, and this RNA is then used to make a protein. In many simple cases, people expect that if a gene is turned down at the RNA level, the protein made from it should also go down. But in real biological systems, that relationship is often not so direct. Cells can control how much RNA is made, how it is processed, how efficiently it is translated into protein, and how quickly proteins are broken down. Because of that, changes in RNA levels and protein levels do not always match.
In Dr. Raj lab’s data, transcription and protein levels did not show a strong correlation, which suggests that FXS and FXTAS involve more complex, non-linear regulation. Some genes involved in mRNA processing, splicing, and protein synthesis were increased, while others related to synapse organization and synaptic vesicles were decreased. In the brain proteome data, they saw many changes in proteins linked to cytoskeletal organization, which is important for maintaining cell shape, structure, and communication. Overall, this indicates that the disease is affecting not just which genes are switched on, but also how their messages are processed and how proteins are ultimately produced and controlled. In particular, the impaired function of FMRP in the translational regulation of numerous target genes may contribute to these complex phenotypic outcomes in FXS and FXTAS patients.
The phospho-proteomics results add another layer to this picture. Phosphorylation is a chemical modification that can act like an on/off switch for proteins, changing their activity without changing how much protein is present. They found hundreds of proteins with altered phosphorylation, many of them involved in synaptic function. This means that even when the amount of a protein stayed the same, its behavior may have changed. Taken together, these findings suggest that FXS and FXTAS are driven by changes in both protein abundance and protein regulation, especially in pathways important for synapses and brain cell structure.
