Endosomes and Lysosomes in Neuropathology: Molecular Mechanisms, Disease Implications, and Therapeutic Interventions

Endosomes and lysosomes are central regulators of protein and lipid sorting, trafficking, recycling, degradation, and cellular homeostasis. As early endosomes mature into late endosomes, they fuse with lysosomes to complete degradation and recycling processes to maintain cellular homeostasis. Disruptions in the endo-lysosomal system are implicated in a range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and lysosomal storage disorders. Recent scientific advancements have significantly improved our understanding of the role of endosomes and lysosomes in neuropathology. Mutations in LRRK2 can impair lysosomal function and promote the accumulation of toxic α-synuclein species in Parkinson's disease, while presenilin 1 mutations have been associated with altered lysosomal acidification and amyloid-β accumulation in Alzheimer's disease. Additionally, the transcription factor EB (TFEB), a key regulator of lysosomal biogenesis and autophagy, has emerged as a potential therapeutic target because its activation can enhance the clearance of pathological aggregates. At the same time, advances in spatial and single-cell omics, patient-derived and induced pluripotent stem cell models, and live-cell imaging are revealing cell-type-specific and disease-stage-specific alterations in endo-lysosomal biology. However, important questions remain regarding how these defects interact with autophagy, neuroinflammation, mitochondrial dysfunction, and intercellular communication in the human brain.This Research Topic aims to explore the molecular and cellular mechanisms underlying endosome and lysosome dysfunction in the brain. Particular emphasis will be placed on how defects in endosomal maturation, lysosomal acidification, cargo degradation, membrane trafficking, and lysosome-autophagy regulation influence disease initiation and progression. Exosomes, which originate from intraluminal vesicles within multivesicular bodies, will also be considered. These vesicles may be directed toward lysosomal degradation or released when multivesicular bodies fuse with the plasma membrane, thereby contributing to cellular communication and the spread of disease-associated proteins and nucleic acids. The Research Topic will highlight emerging biomarkers and therapeutic approaches, including small-molecule modulators, gene and RNA-based therapies, extracellular-vesicle-based strategies, and interventions targeting TFEB, LRRK2, lysosomal activity, or related pathways.To gather further insights into endosome and lysosome biology in the brain, this Research Topic will cover mechanistic, translational, and therapeutic studies of endo-lysosomal dysfunction across neurodegenerative and lysosomal storage disorders. Contributions may address, but are not limited to, the following themes:• Endosomal maturation, trafficking, and recycling in neurodegenerative disease• Lysosomal dysfunction, impaired acidification, and defective cargo degradation, including regulators such as LRRK2, presenilin 1, and TFEB• Exosome biogenesis, cargo sorting, and release, and the role of extracellular vesicles in propagating pathological proteins and nucleic acids• Cell-type-specific and disease-stage-specific alterations in endo-lysosomal function, characterized through proteomic, lipidomic, single-cell, or spatial approaches, and modeled in patient-derived, iPSC, organoid, or in vivo systems• Therapeutic strategies targeting endo-lysosomal pathways, including small-molecule, gene, RNA, and extracellular-vesicle-based approaches, and applications for lysosomal storage disorders such as Niemann–Pick disease Topic editors: Ayan Mohamud Yusuf, Dirk M. Hermann, Xianshuang Liu Source: https://www.frontiersin.org/research-topics/85391/endosomes-and-lysosomes-in-neuropathology-molecular-mechanisms-disease-implications-and-therapeutic-interventions