The Alzheimer’s gene SORL1 is a key regulator of endosomal recycling in human neurons

ABSTRACT: Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell derived neurons (hiPSC-Ns) to test this hypothesis. In SORL1 deficient (SORL1KO) cell lines, we map the trafficking of the glutamate receptor and the BDNF neurotrophic receptor, two kinds of transmembrane proteins that depend on endosomal recycling and that are linked to AD pathophysiology. We find that as with APP, SORL1 is required for efficient endosomal recycling of the glutamate receptor AMPA1 (GLUA1) and the BDNF receptor Tropomyosin-related kinase B (TRKB). Next, we used cell lines engineered to overexpress SORL1 and find that increased SORL1 expression enhances recycling for APP and GLUA1. Finally, we performed an unbiased transcriptomic screen of SORL1KO neurons and the data further support SORL1’s role in endosomal recycling. We observed altered expression networks that regulate cell surface trafficking and neurotrophic signaling. Collectively, and together with other recent observations, these findings suggest that SORL1 is a key and broad regulator of retromer-dependent endosomal recycling in neurons, a conclusion that has both pathogenic and therapeutic implications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180793 | GEO | 2022/03/01

REPOSITORIES: GEO