VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress

Introduction Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.