A Computational Atlas of Mutational Vulnerability Highlights Convergent Prion-Like and Aggregation-Associated Features in Neurodegenerative Proteins

Cross-protein mutational susceptibility is not well understood, despite the fact that neurodegenerative diseases are caused by the misfolding, aggregation, and functional disruption of several proteins. Integrative analyses that combine mutational susceptibility patterns across several proteins implicated in neurodegenerative illness are lacking, despite the fact that prior research has concentrated on specific disease-associated proteins. Here, we offer a computational atlas of mutational vulnerability that includes 22 proteins associated with important neurodegenerative diseases, such as spinocerebellar ataxias, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.We conducted a cross-protein comparative analysis to find regions that are disproportionately sensitive to amino acid substitutions using curated human variant data from UniProt, prion-like domain predictions, sequence-derived mutational sensitivity profiling, and aggregation-prone region mapping. Several structurally and functionally diverse proteins, many of which are still underrepresented in naturally occurring human variation, share susceptibility regions, as our results demonstrate. Specifically, proteins like ATXN2, OPTN, and MATR3 show strong mutational sensitivity and little overlap with known human variants, indicating unknown loci with potentially harmful effects. Furthermore, mechanistic connections between intrinsic sequence instability and pathological misfolding are strengthened by the selective enrichment of susceptible residues in prion-like and aggregation-prone areas. A resource for prioritizing proteins and regions for mutational screening, structural biophysics, and therapeutic targeting is provided by this study, which unifies mutational, structural, and aggregation-prone characteristics into a unified framework. In addition to confirming established risk loci, the cross-protein mutational vulnerability atlas identifies obscure locations that require more investigation. More generally, our method creates a scalable framework for mapping sequence-derived susceptibility across protein families, providing a link between mechanistic understanding of the causes of neurodegeneration and computational predictions. This study offers a strategic roadmap for upcoming experimental and translational research in neurodegenerative illnesses and emphasizes the value of integrative, multi-protein investigations in comprehending disease causation. All findings are derived from computational analyses and are intended to guide, rather than replace, experimental validation.