Protein Quality Control in Neurodegeneration and Metabolic Disease

Cellular protein homeostasis (proteostasis) is sustained by coordinated quality control systems that regulate protein folding, trafficking, and degradation. Disruption of these mechanisms leads to the accumulation of misfolded or aggregated proteins, triggering proteotoxic stress, inflammation, and progressive tissue dysfunction. Impaired proteostasis is a defining feature of both neurodegenerative disorders, marked by toxic protein inclusions, and metabolic diseases associated with chronic endocrine and inflammatory imbalance. Although traditionally studied as distinct conditions, these diseases share convergent molecular pathways involving molecular chaperones, the ubiquitin–proteasome system, autophagy–lysosomal degradation, and endoplasmic reticulum stress responses. Increasing evidence suggests that these interconnected “proteostasis circuits” operate across tissues to maintain cellular resilience. Understanding how their failure drives disease may reveal shared mechanisms and broadly applicable therapeutic opportunities.The goal of this Research Topic is to establish protein quality control pathways as a unifying biological framework connecting neurodegenerative and metabolic diseases. We aim to integrate molecular, cellular, and translational studies that explain how disruptions in proteostasis circuits promote dysfunction across the brain, liver, adipose tissue, bone, and immune systems. By studying mechanisms such as impaired chaperone activity, defective proteasomal degradation, altered autophagy, mitochondrial stress, and chronic inflammatory signaling, this collection aims to reveal common drivers of disease progression that transcend organ boundaries. The main objective is to link fundamental discovery with therapeutic development. We encourage investigations that identify actionable targets and innovative strategies to restore proteostasis, including biologics, monoclonal antibodies, small-molecule modulators, gene-based therapies, and targeted protein degradation technologies. Through interdisciplinary collaboration, this Topic aims to accelerate translation of mechanistic insights into effective interventions. Ultimately, we hope to define proteostasis restoration as a practical and scalable approach to preventing and treating chronic, age-related disorders with significant global health burden.We invite submissions of original research articles, reviews, perspectives, and methodological reports addressing protein quality control mechanisms in neurodegenerative and metabolic diseases. Topics of interest include molecular chaperones and folding networks; ubiquitin–proteasome and lysosomal pathways; autophagy, mitophagy, and organelle surveillance; ER stress and unfolded protein response signaling; protein aggregation and clearance; immunometabolic cross-talk; aging-related proteostasis decline; and biomarker discovery. Translational studies evaluating therapeutic strategies such as monoclonal antibodies, biologics, targeted protein degradation platforms, and small-molecule modulators are strongly encouraged. Interdisciplinary approaches using cell and animal models, human samples, omics technologies, computational analyses, or early clinical investigations are welcome. Submissions should emphasize mechanistic insight, therapeutic relevance, or integration across organ systems. Contributions that bridge neuroscience and metabolism to reveal shared disease pathways will be prioritized to promote a comprehensive understanding of proteostasis circuits in health and disease. Topic editors: Anusha Rani Pallapati, Rauf Latif, Ramesh NIMMA Source: https://www.frontiersin.org/research-topics/75137/protein-quality-control-in-neurodegeneration-and-metabolic-disease