Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 38, Pages 13461-13466Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503689102
Keywords
endocytic receptors; knockout mouse; neurodegeneration; Vps10p-domain receptors
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sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid) beta-peptide (A beta), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A beta, whereas ablation of sorLA expression in knockout mice results in increased levels of A beta in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A beta and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A beta production and plaque formation and promote spontaneous AD.
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