Protein function is shaped by cellular context, yet most protein representations and interaction maps remain context-agnostic. Here we present ProtScape, a multiscale graph-learning framework integrating global protein interactions, cell-type gene expression and protein language models to learn context-specific representations and infer interactomes across more than 200 cell types. ProtScape substantially outperforms existing approaches in interaction reconstruction, increasing the area under the precision–recall curve by 40 percentage points. Its predicted interactions were supported by held-out continuous STRING global evidence, while its representations recovered higher-order protein organisation. In patient-derived amyotrophic lateral sclerosis motor neurons, ProtScape revealed stage-specific network changes implicating RAB-dependent trafficking as a candidate early disease mechanism. In Parkinson’s disease, it recovered clinically supported therapeutic targets from a proteome-wide search space 16-fold smaller than that required by competing representations. Together, ProtScape provides a scalable framework for translating context-specific interactome organisation into experimentally testable disease mechanisms and therapeutic hypotheses.
Alois Thomas, Lisa Fournier, Vincent Jung et al.· bioRxiv· 0 citations
Abstract Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding ‘junk’, remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript’s translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR’s significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR’s increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.
Chloe Y Wang, Stephanie Taylor, Virenkumar A Pandya et al.· Brain : a journal of neurolo...· 0 citations
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