Efficient endosomal trafficking, autophagy, and lysosomal degradation are essential for maintaining cellular homeostasis, particularly in neurons, by clearing aggregated proteins and damaged organelles. In neurodegenerative diseases such as AD, ALS, PD and FTD, these clearance pathways are often disrupted, leading to the accumulation of misfolded proteins and dysfunctional organelles that contribute to cellular toxicity. The endosome-lysosome system, which degrades intra- and extracellular material, is especially critical. In AD, for instance, accumulation of APP toxic peptides impairs endosomal trafficking and lysosomal function, disrupting waste clearance and cellular signaling. Similarly, autophagy is often compromised, impairing autophagic flux and allowing toxic aggregates to build up. These impairments exacerbate neuronal damage and are central to disease pathology. As a result, targeting endo-lysosomal and autophagic pathways offers a promising therapeutic approach for restoring intracellular clearance mechanisms and improving neuronal health in neurodegenerative disorders.

There is a need for better characterization of endosomal-lysosomal and autophagic dysfunction dynamics. To make significant progress in this area, the goal of publishing a series of research articles would be to deepen our understanding of how endosomal trafficking, autophagy, and lysosomal degradation systems are disrupted at molecular level in neurodegenerative diseases. These publications would provide valuable insights into the molecular mechanisms behind pathway dysfunction, explore innovative pharmacological and genetic therapeutic strategies, and offer translational approaches to restore intracellular trafficking and clearance mechanisms. By integrating findings from diverse studies and promoting interdisciplinary approaches, this research collection could provide insights into novel therapeutic avenues for AD, ALS, PD, FTD, and other neurodegenerative disorders. These efforts may lead to a better understanding of disease pathogenesis and guide the development of effective therapies to stop and slow down the progression of neurodegenerative diseases.

This research topic article collection will cover a wide range of issues related to endo-lysosomal and autophagic dysfunctions in neurodegenerative diseases, including, but not limited to:

• Mechanisms underlying intracellular vesicular trafficking defects in neurodegenerative disorders
• Investigating endosomopathies, focusing on defects in endocytic uptake and trafficking in neurodegenerative diseases
• Exploring the link between cognitive decline and neuronal endosomal signaling defects in neurodegenerative diseases
• Lysosomal and autophagic degradation impairments in the context of neurodegenerative disorders
• Impaired mitophagy and its role in neurodegeneration
• Pharmacological and genetic interventions aimed at restoring lysosomal and autophagosomal function as potential therapeutic strategies for neurodegenerative proteinopathies
• Identification of GWAS-risk genes involved in the impairment of endosomal trafficking, autophagy, and lysosomal function in neurodegenerative contexts.
• Development of in vivo models to study the function of endo-lysosomal GWAS-risk genes in neurodegeneration.

This collection aims to provide a comprehensive overview of the current research and emerging therapeutic approaches in these critical areas of neurodegenerative disease mechanisms.

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Impairment of endosomal trafficking, autophagy, and lysosomal function in neurodegenerative disorders