Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 35, Pages 18283-18298Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.703157
Keywords
endosome; intracellular trafficking; membrane transport; Parkinson disease; protein sorting; retromer
Categories
Funding
- National Health and Medical Research Council (NHMRC) of Australia [APP1025538, APP1037320, APP1042082, APP1045092, APP1058734]
- Australian Research Council [DP120103930]
- Centre of Excellence in Convergent Bio-Nano Science and Technology
- ANZ Trustees National Medical Program Grant from Judith Jane Mason and Harold Stannett Williams Memorial Foundation
- NHMRC [APP1061574, APP1058565, APP1041929]
- ARC Future Fellowship [FT100100027]
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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 -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.
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