Muskelin Coordinates PrP Lysosome versus Exosome Targeting and Impacts Prion Disease Progression
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Muskelin Coordinates PrP Lysosome versus Exosome Targeting and Impacts Prion Disease Progression. / Heisler, Frank F; Pechmann, Yvonne; Wieser, Ines; Altmeppen, Hermann C; Veenendaal, Leonhard; Muhia, Mary; Schweizer, Michaela; Glatzel, Markus; Krasemann, Susanne; Kneussel, Matthias.
in: NEURON, Jahrgang 99, Nr. 6, 19.09.2018, S. 1155-1169.e9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Muskelin Coordinates PrP Lysosome versus Exosome Targeting and Impacts Prion Disease Progression
AU - Heisler, Frank F
AU - Pechmann, Yvonne
AU - Wieser, Ines
AU - Altmeppen, Hermann C
AU - Veenendaal, Leonhard
AU - Muhia, Mary
AU - Schweizer, Michaela
AU - Glatzel, Markus
AU - Krasemann, Susanne
AU - Kneussel, Matthias
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - Cellular prion protein (PrPC) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrPC undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrPC and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrPC trafficking that also link intracellular and extracellular PrPC turnover. PrPC associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrPC transport and facilitates lysosomal degradation over exosomal PrPC release. Muskelin gene knockout consequently causes PrPC accumulation at the neuronal surface and on secreted exosomes. Moreover, prion disease onset is accelerated following injection of pathogenic prions into muskelin knockout mice. Our data identify an essential checkpoint in PrPC turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.
AB - Cellular prion protein (PrPC) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrPC undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrPC and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrPC trafficking that also link intracellular and extracellular PrPC turnover. PrPC associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrPC transport and facilitates lysosomal degradation over exosomal PrPC release. Muskelin gene knockout consequently causes PrPC accumulation at the neuronal surface and on secreted exosomes. Moreover, prion disease onset is accelerated following injection of pathogenic prions into muskelin knockout mice. Our data identify an essential checkpoint in PrPC turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.
KW - Journal Article
U2 - 10.1016/j.neuron.2018.08.010
DO - 10.1016/j.neuron.2018.08.010
M3 - SCORING: Journal article
C2 - 30174115
VL - 99
SP - 1155-1169.e9
JO - NEURON
JF - NEURON
SN - 0896-6273
IS - 6
ER -