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

Abstract

Background: 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. We examined endosomal recycling of three transmembrane proteins linked to AD pathophysiology: APP, the BDNF receptor Tropomyosin-related kinase B (TRKB), and the glutamate receptor subunit AMPA1 (GLUA1). Methods: We used isogenic hiPSCs engineered to have SORL1 depleted or to have enhanced SORL1 expression. We differentiated neurons from these cell lines and mapped the trafficking of APP, TRKB and GLUA1 within the endosomal network using confocal microscopy. We also performed cell surface recycling and lysosomal degradation assays to assess the functionality of the endosomal network. Finally, we analyzed alterations in gene expression in SORL1 depleted neurons using RNA-sequencing. Results: We find that as with APP, endosomal trafficking of GLUA1 and TRKB is impaired by loss of SORL1. Conversely, increased SORL1 expression enhances endosomal recycling for APP and GLUA1. Our unbiased transcriptomic data further support SORL1's role in endosomal recycling. We observe altered expression networks that regulate cell surface trafficking and neurotrophic signaling Conclusion: 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 for Alzheimer's disease.

The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease

“…Retromer is considered a “master conductor” of endosomal trafficking ( Burd and Cullen, 2014 ) because it regulates the two pathways whereby cargo is recycling out of endosomes: from the endosome back to the cell surface, and from the endosome back to the TGN ( trans -Golgi network). APP and GluA1 are neuronal endosomal cargo that typify the first pathway, and based on older ( Small and Petsko, 2015 ) and newer studies ( Mishra et al, 2021 ), SORL1 (sortilin-related receptor1) can act a retromer-receptor that allows the retromer coat to interact with this cargo. We, therefore, took advantage of our depletion-repletion paradigm to investigate SORL1.…”

Endo-lysosomal dysfunction in neurodegenerative diseases: opinion on current progress and future direction in the use of exosomes as biomarkers

“…For instance, late-onset risk genes such as BIN1 , PICALM , CD2AP and SORL1 play various functions in endosomal trafficking [ 25 , 32 – 35 ]. Cell biology studies from our group and others demonstrated that proteins such as Retromer [ 36 ] and its associated receptor, SORL1, play a key role in the trafficking of cargo out of the endosome towards the plasma membrane [ 37 – 39 ], a process impaired in AD and critical for neuronal function. These discoveries reveal a promising avenue for biomarker development focused on endosomal trafficking, which we are currently investigating [ 40 ].…”