To investigate the phosphoproteomic changes in TSC patient surgical tuber and SEGA tissue to understand the molecular pathogenesis of neurological symptoms associated with Tuberous Sclerosis Complex, which may inform future therapeutic strategies.
Key Findings:
Significant proteomic changes in tuber tissue indicated altered mitochondrial processes.
In SEGA tissue, evidence of increased ribosome biogenesis and activation of neuroinflammatory processes was found.
Phosphoproteomic analysis revealed perturbed cytoskeleton organization and neuronal function in tubers, with no evidence of mTORC1 activation.
In SEGAs, phosphorylation of canonical mTORC1 targets was strongly increased, identifying over 2000 novel mTORC1 targets.
Gene ontology analysis indicated increased phosphorylation of RNA metabolism/mRNA splicing proteins in SEGAs.
RNA-sequencing data showed large-scale changes in mRNA transcript splicing in SEGA tissue.
Interpretation:
The study highlights the distinct molecular alterations in TSC-related brain lesions, particularly the activation of mTORC1 in SEGAs, which leads to significant changes in RNA metabolism and splicing, potentially contributing to neurological symptoms and suggesting avenues for future research.
Limitations:
The study primarily focuses on surgical samples, which may not represent the full spectrum of TSC pathology and could limit the generalizability of findings.
Findings are based on a limited number of patient samples, which may affect generalizability.
Conclusion:
The activation of mTORC1 in SEGAs leads to profound changes in the phosphoproteome and RNA splicing mechanisms, suggesting potential therapeutic targets for managing neurological symptoms in TSC patients, warranting further investigation.
by Marie Girodengo, Simeon R. Mihaylov, Katarzyna Klonowska, Laura Mantoan Ritter, Helen R. Flynn, J. Mark Skehel, Elias Bou Farhat, Eleonora Aronica, Matthew White, David J. Kwiatkowski, Sila K. Ultanir, Joseph M. Bateman
