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

Swati Mishra, Allison Knupp, Marcell P. Szabo, Charles A. Williams, Chizuru Kinoshita, Dale W. Hailey, Yuliang Wang, View ORCID ProfileJessica E. Young
doi: https://doi.org/10.1101/2021.07.26.453861
Swati Mishra
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Allison Knupp
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Marcell P. Szabo
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Charles A. Williams
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Chizuru Kinoshita
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Dale W. Hailey
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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Yuliang Wang
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
3School of Computer Science and Engineering University of Washington Seattle WA, 98195, USA
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Jessica E. Young
1Department of Laboratory Medicine and Pathology University of Washington Seattle WA, 98195, USA
2Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA, 98195, USA
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  • ORCID record for Jessica E. Young
  • For correspondence: jeyoung@uw.edu
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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 in both SORL1 depleted and overexpressing neurons. 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. We show that trafficking of all three cargo to late endosomes and lysosomes is affected by manipulating SORL1 expression. We also show that depletion of SORL1 significantly impacts the endosomal recycling pathway for APP and GLUA1 at the level of the recycling endosome and trafficking to the cell surface. This has a functional effect on neuronal activity as shown by multi-electrode array (MEA). 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 in SORL1 depleted neurons.

Conclusion Collectively, and together with other recent observations, these findings suggest that SORL1 is a broad regulator of retromer-dependent endosomal recycling in neurons, a conclusion that has both pathogenic and therapeutic implications for Alzheimer’s disease.

Competing Interest Statement

The authors have declared no competing interest.

  • ABBREVIATIONS

    AD
    Alzheimer’s Disease
    SORL1
    Sortilin-related receptor 1
    SORLA
    Sortilin-related receptor with A-type repeats
    APP
    Amyloid Precursor Protein
    TRKB
    Tropomyosin Related Kinase B
    GLUA1
    Glutamate receptor subunit AMPA1
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    OE
    Overexpression
    KO
    Knock-out
    WT
    Wild-type
    LAMP1
    Lysosome-associated membrane glycoprotein 1
    M6PR
    mannose-6-phosphate receptor
    GGA
    Golgi-Localized g-Ear-Containing ARF-Binding
    Rab
    Ras-related protein.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted January 11, 2022.
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    The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons
    Swati Mishra, Allison Knupp, Marcell P. Szabo, Charles A. Williams, Chizuru Kinoshita, Dale W. Hailey, Yuliang Wang, Jessica E. Young
    bioRxiv 2021.07.26.453861; doi: https://doi.org/10.1101/2021.07.26.453861
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    The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons
    Swati Mishra, Allison Knupp, Marcell P. Szabo, Charles A. Williams, Chizuru Kinoshita, Dale W. Hailey, Yuliang Wang, Jessica E. Young
    bioRxiv 2021.07.26.453861; doi: https://doi.org/10.1101/2021.07.26.453861

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