Biology subjects

Pinto, F. R.

Publications and source records attributed to Pinto, F. R..

5 recordsLinked to original sources

bioRxiv2025

When neighbours play a role: a systems-level analysis of protein interactions conditioning cancer driver mutation effects

BackgroundCancer is driven by the accumulation of somatic mutations, including driver mutations that confer a selective advantage to cancer cells. Driver proteins operate within complex interaction networks, and their activity is conditioned by neighbour proteins. Understanding the interplay between driver mutations and the expression of their neighbour proteins can provide insights into cancer biology and potential therapeutic targets. MethodsWe assessed associations between expression of neighbour proteins and driver mutation status, comparing both between and within cancer types. We further evaluated if neighbours were enriched in significant associations with multiple drivers and characterised the impact of neighbour expression on overall survival for all cancer types. ResultsWe found a significant correlation between the number of driver associations a neighbour gene has and the number of sign-coherent survival associations, particularly for neighbours enriched in positive associations, where high neighbour expression correlated with increased driver mutations and poorer survival. We identified 119 neighbours enriched in positive driver associations with at least two unfavourable survival associations and 25 neighbours enriched in negative driver associations with at least two favourable survival associations. ConclusionsOur study systematically identified neighbours associated with driver mutation status. Complementary evidence from survival analysis and the literature suggests that neighbours enriched in driver associations can be further explored as drug target candidates. Significance StatementCancers are caused by mutations in driver genes. The impact of those mutations in the cell can be influenced by other proteins in the cell that physically interact with the mutated protein. In this work, we analysed cancer patient data to uncover such neighbour proteins that may influence the outcome of driver mutations. We discovered a subset of neighbour proteins that are associated with mutations in multiple cancer drivers and, simultaneously, are associated with changes in survival times of patients for multiple cancer types. These neighbour proteins may help explain why some driver mutations are more common in certain cancer types. We also propose that these neighbour proteins should be explored as candidate drug targets for cancer therapy.

cancer biology↗

bioRxiv2024

Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging

Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.

bioengineering↗

bioRxiv2024

Subcellular, biochemical and biophysical alterations in two glial cell models of ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a developmental and degenerative disorder caused by loss-of-function mutations in the gene that codifies for the sacsin chaperone. Sacsin was initially described as a neuronal protein but is found in various cell types, including astroglial, microglial, kidney, and skin cell lines. We and others have shown that virtually all cell and animal models of ARSACS show disruption of intermediate filament (IF) cytoskeleton and organelle distribution. This article extends previous observations from our lab on the C6 astroglial-like model and describes the development and characterization of a new human microglial cell model based on HMC3 cells. HMC3 cells knocked out for sacsin show similar alterations to C6 astroglial-like cells: aberrant distribution of IF network and organelles, downregulation of developmental transcription factors STAT3 and Smad1, and alterations in autophagy machinery and markers of intracellular stress, resulting in morphological changes. Our results extend previous observations suggesting a possible role for glial cells in ARSACS and provide new tools to understand the glial-specific mechanisms involved in this pathology.

biochemistry↗

bioRxiv2022

Analysis of pre-symptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration

Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown. Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, our integrative approach revealed they exert a concerted effect on protein functional modules, acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes. The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.

neuroscience↗

bioRxiv2017

A Mathematical Model of the Phosphoinositide Pathway

Phosphoinositides are signaling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all known species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the phosphoinositide pathway and most known dynamic phenomena. Furthermore, sensitivity analysis demonstrates model robustness to moderate alterations in any of the parameters. Model analysis suggest that the greatest contributor to PI(4,5)P2 production is a flux representing the direct transformation of PI into PI(4,5)P2 and is also responsible for the maintenance of this pool when PI(4)P is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P2 production. The model was validated with data from siRNA screens that knocked down the expression of several enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel, ENaC, which is activated by PI(4,5)P2. Moderating ENaC activity can have a therapeutic effect in Cystic Fibrosis (CF) patients. Our model suggests control strategies where the activities of the enzyme PIP5KI or the PI4K+PIP5KI+DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P2 levels while avoiding undesirable alterations in other phosphoinositide pools.\n\nAbbreviations

systems biology↗