Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain

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Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain. / Dumanis, Sonya B.; Burgert, Tilman; Caglayan, Safak; Füchtbauer, Annette; Füchtbauer, Ernst Martin; Schmidt, Vanessa; Willnow, Thomas E.

I: Journal of Neuroscience, Bind 35, Nr. 37, 2015, s. 12703-12713.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Dumanis, SB, Burgert, T, Caglayan, S, Füchtbauer, A, Füchtbauer, EM, Schmidt, V & Willnow, TE 2015, 'Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain', Journal of Neuroscience, bind 35, nr. 37, s. 12703-12713. https://doi.org/10.1523/JNEUROSCI.0427-15.2015

APA

Dumanis, S. B., Burgert, T., Caglayan, S., Füchtbauer, A., Füchtbauer, E. M., Schmidt, V., & Willnow, T. E. (2015). Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain. Journal of Neuroscience, 35(37), 12703-12713. https://doi.org/10.1523/JNEUROSCI.0427-15.2015

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MLA

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Author

Dumanis, Sonya B. ; Burgert, Tilman ; Caglayan, Safak ; Füchtbauer, Annette ; Füchtbauer, Ernst Martin ; Schmidt, Vanessa ; Willnow, Thomas E. / Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain. I: Journal of Neuroscience. 2015 ; Bind 35, Nr. 37. s. 12703-12713.

Bibtex

@article{3d0018645bd942d3913d59ebde30f9c5,
title = "Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain",
abstract = "SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking forSORLAactivity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptormediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes.",
keywords = "Adaptors, APP processing, Protein transport, Retromer, SORLA, VPS10P domain receptors",
author = "Dumanis, {Sonya B.} and Tilman Burgert and Safak Caglayan and Annette F{\"u}chtbauer and F{\"u}chtbauer, {Ernst Martin} and Vanessa Schmidt and Willnow, {Thomas E.}",
year = "2015",
doi = "10.1523/JNEUROSCI.0427-15.2015",
language = "English",
volume = "35",
pages = "12703--12713",
journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "37",

}

RIS

TY - JOUR

T1 - Distinct functions for anterograde and retrograde sorting of SORLA in amyloidogenic processes in the brain

AU - Dumanis, Sonya B.

AU - Burgert, Tilman

AU - Caglayan, Safak

AU - Füchtbauer, Annette

AU - Füchtbauer, Ernst Martin

AU - Schmidt, Vanessa

AU - Willnow, Thomas E.

PY - 2015

Y1 - 2015

N2 - SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking forSORLAactivity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptormediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes.

AB - SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking forSORLAactivity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptormediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes.

KW - Adaptors

KW - APP processing

KW - Protein transport

KW - Retromer

KW - SORLA

KW - VPS10P domain receptors

UR - http://www.scopus.com/inward/record.url?scp=84941760281&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0427-15.2015

DO - 10.1523/JNEUROSCI.0427-15.2015

M3 - Journal article

VL - 35

SP - 12703

EP - 12713

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 37

ER -