Muskelin Coordinates PrPC Lysosome versus Exosome Targeting and Impacts Prion Disease Progression

Neuron
Frank F HeislerMatthias Kneussel

Abstract

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.

Citations

Jul 10, 2019·Scientific Reports·Matthew E R MaitlandCaroline Schild-Poulter
Jul 8, 2020·Expert Opinion on Therapeutic Targets·Arianna Colini BaldeschiGiuseppe Legname
Aug 11, 2020·Cell Communication and Signaling : CCS·Xueqiang PengHangyu Li
Jun 12, 2019·Molecular Neurodegeneration·Luke S WatsonCatrina Sims-Robinson
Jun 18, 2020·Frontiers in Molecular Neuroscience·Zhiqi SongChuan Qin
Oct 23, 2019·Frontiers in Molecular Neuroscience·Wanying LiuJunping Zhang
Oct 24, 2020·International Journal of Molecular Sciences·Rodrigo Nunes AlvesMarilene Hohmuth Lopes
Mar 13, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiao-Tong WangYu-He Yuan
Apr 2, 2021·The EMBO Journal·Maria Elena CicardiDavide Trotti
Oct 1, 2020·International Journal of Molecular Sciences·Hajar Miranzadeh Mahabadi, Changiz Taghibiglou
Apr 26, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jing RuanXu Wang
Jun 6, 2021·Journal of Experimental & Clinical Cancer Research : CR·Xueqiang PengHangyu Li
May 18, 2021·IScience·Matthias KneusselFrank F Heisler
Aug 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Matthew E R MaitlandCaroline Schild-Poulter
Jan 28, 2022·Cell and Tissue Research·Behnam MohammadiHermann Clemens Altmeppen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.

Brain developing: Influences & Outcomes

This feed focuses on influences that affect the developing brain including genetics, fetal development, prenatal care, and gene-environment interactions. Here is the latest research in this field.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Related Papers

Nature Communications
Keiji UchiyamaSuehiro Sakaguchi
Future Medicinal Chemistry
Emiliano Biasini, D A Harris
Proceedings of the National Academy of Sciences of the United States of America
Benoît FévrierGraça Raposo
© 2022 Meta ULC. All rights reserved