Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

• Published in: The Journal of biological chemistry Vol. 291; no. 35; pp. 18283 - 18298
• Main Authors: Follett, Jordan, Bugarcic, Andrea, Yang, Zhe, Ariotti, Nicholas, Norwood, Suzanne J., Collins, Brett M., Parton, Robert G., Teasdale, Rohan D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.08.2016; American Society for Biochemistry and Molecular Biology
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amino Acid Substitution; endosome; Endosomes; HeLa Cells; Humans; intracellular trafficking; membrane transport; Molecular Bases of Disease; Mutation, Missense; Parkinson disease; Parkinson Disease - genetics; Parkinson Disease - metabolism; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; protein sorting; retromer; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Parkinson disease; intracellular trafficking; membrane transport; endosome; retromer; protein sorting
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.703157

Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting. Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular α-synuclein-positive aggregates, a hallmark of Parkinson disease. Overall, the Vps35 R524W-containing retromer has a decreased endosomal association, which can be partially rescued by R55, a small molecule previously shown to stabilize the retromer complex, supporting the potential for future targeting of the retromer complex in the treatment of Parkinson disease.