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

Abstract

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. This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target. VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.