Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing
Summary: SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer’s disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early...
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doaj-19746c1d19d847c3a60732df360c1e8c2020-11-25T03:20:37ZengElsevierCell Reports2211-12472020-06-01319Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP ProcessingAllison Knupp0Swati Mishra1Refugio Martinez2Jacquelyn E. Braggin3Marcell Szabo4Chizuru Kinoshita5Dale W. Hailey6Scott A. Small7Suman Jayadev8Jessica E. Young9Department of Pathology, University of Washington, Seattle, WA 98109, USADepartment of Pathology, University of Washington, Seattle, WA 98109, USADepartment of Pathology, University of Washington, Seattle, WA 98109, USADepartment of Neurology, University of Washington, Seattle, WA 98195, USADepartment of Pathology, University of Washington, Seattle, WA 98109, USADepartment of Pathology, University of Washington, Seattle, WA 98109, USAInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USATaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY 10032, USADepartment of Neurology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USADepartment of Pathology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Corresponding authorSummary: SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer’s disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early endosome enlargement, a hallmark cytopathology of AD. There is no effect of SORL1 depletion on endosome size in hiPSC microglia, suggesting a selective effect on neuronal endosomal trafficking. We validate defects in neuronal endosomal traffic by showing altered localization of amyloid precursor protein (APP) in early endosomes, a site of APP cleavage by the β-secretase (BACE). Inhibition of BACE does not rescue endosome enlargement in SORL1-deficient neurons, suggesting that this phenotype is independent of amyloidogenic APP processing. Our data, together with recent findings, underscore how sporadic AD pathways regulating endosomal trafficking and autosomal-dominant AD pathways regulating APP cleavage independently converge on the defining cytopathology of AD.http://www.sciencedirect.com/science/article/pii/S2211124720306963Alzheimer's diseasehuman induced pluripotent stem cellsSORL1early endosomes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Allison Knupp Swati Mishra Refugio Martinez Jacquelyn E. Braggin Marcell Szabo Chizuru Kinoshita Dale W. Hailey Scott A. Small Suman Jayadev Jessica E. Young |
spellingShingle |
Allison Knupp Swati Mishra Refugio Martinez Jacquelyn E. Braggin Marcell Szabo Chizuru Kinoshita Dale W. Hailey Scott A. Small Suman Jayadev Jessica E. Young Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing Cell Reports Alzheimer's disease human induced pluripotent stem cells SORL1 early endosomes |
author_facet |
Allison Knupp Swati Mishra Refugio Martinez Jacquelyn E. Braggin Marcell Szabo Chizuru Kinoshita Dale W. Hailey Scott A. Small Suman Jayadev Jessica E. Young |
author_sort |
Allison Knupp |
title |
Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing |
title_short |
Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing |
title_full |
Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing |
title_fullStr |
Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing |
title_full_unstemmed |
Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing |
title_sort |
depletion of the ad risk gene sorl1 selectively impairs neuronal endosomal traffic independent of amyloidogenic app processing |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2020-06-01 |
description |
Summary: SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer’s disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early endosome enlargement, a hallmark cytopathology of AD. There is no effect of SORL1 depletion on endosome size in hiPSC microglia, suggesting a selective effect on neuronal endosomal trafficking. We validate defects in neuronal endosomal traffic by showing altered localization of amyloid precursor protein (APP) in early endosomes, a site of APP cleavage by the β-secretase (BACE). Inhibition of BACE does not rescue endosome enlargement in SORL1-deficient neurons, suggesting that this phenotype is independent of amyloidogenic APP processing. Our data, together with recent findings, underscore how sporadic AD pathways regulating endosomal trafficking and autosomal-dominant AD pathways regulating APP cleavage independently converge on the defining cytopathology of AD. |
topic |
Alzheimer's disease human induced pluripotent stem cells SORL1 early endosomes |
url |
http://www.sciencedirect.com/science/article/pii/S2211124720306963 |
work_keys_str_mv |
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