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GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

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GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice. / Puig, Berta; Altmeppen, Hermann C; Linsenmeier, Luise; Chakroun, Karima; Wegwitz, Florian; Piontek, Ulrike K; Tatzelt, Jörg; Bate, Clive; Magnus, Tim; Glatzel, Markus.

In: PLOS PATHOG, Vol. 15, No. 1, 01.2019, p. e1007520.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Puig, B, Altmeppen, HC, Linsenmeier, L, Chakroun, K, Wegwitz, F, Piontek, UK, Tatzelt, J, Bate, C, Magnus, T & Glatzel, M 2019, 'GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice', PLOS PATHOG, vol. 15, no. 1, pp. e1007520. https://doi.org/10.1371/journal.ppat.1007520

APA

Puig, B., Altmeppen, H. C., Linsenmeier, L., Chakroun, K., Wegwitz, F., Piontek, U. K., Tatzelt, J., Bate, C., Magnus, T., & Glatzel, M. (2019). GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice. PLOS PATHOG, 15(1), e1007520. https://doi.org/10.1371/journal.ppat.1007520

Vancouver

Puig B, Altmeppen HC, Linsenmeier L, Chakroun K, Wegwitz F, Piontek UK et al. GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice. PLOS PATHOG. 2019 Jan;15(1):e1007520. https://doi.org/10.1371/journal.ppat.1007520

Bibtex

@article{74c1dbc0b03e408795160f3749a03aae,
title = "GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice",
abstract = "The cellular prion protein (PrPC) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.",
keywords = "Journal Article, Research Support, Non-U.S. Gov't",
author = "Berta Puig and Altmeppen, {Hermann C} and Luise Linsenmeier and Karima Chakroun and Florian Wegwitz and Piontek, {Ulrike K} and J{\"o}rg Tatzelt and Clive Bate and Tim Magnus and Markus Glatzel",
year = "2019",
month = jan,
doi = "10.1371/journal.ppat.1007520",
language = "English",
volume = "15",
pages = "e1007520",
journal = "PLOS PATHOG",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "1",

}

RIS

TY - JOUR

T1 - GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

AU - Puig, Berta

AU - Altmeppen, Hermann C

AU - Linsenmeier, Luise

AU - Chakroun, Karima

AU - Wegwitz, Florian

AU - Piontek, Ulrike K

AU - Tatzelt, Jörg

AU - Bate, Clive

AU - Magnus, Tim

AU - Glatzel, Markus

PY - 2019/1

Y1 - 2019/1

N2 - The cellular prion protein (PrPC) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.

AB - The cellular prion protein (PrPC) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.ppat.1007520

DO - 10.1371/journal.ppat.1007520

M3 - SCORING: Journal article

C2 - 30608982

VL - 15

SP - e1007520

JO - PLOS PATHOG

JF - PLOS PATHOG

SN - 1553-7366

IS - 1

ER -