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Author Spotlight: Insight Into Advances in Prion Diseases Research

Author Spotlight: Insight Into Advances in Prion Diseases Research

Published on: August 11, 2023

Muskelin Coordinates PrP^C Lysosome versus Exosome Targeting and Impacts Prion Disease Progression

Frank F Heisler¹, Yvonne Pechmann¹, Ines Wieser¹

¹Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.

|September 4, 2018

Abstract:

Cellular prion protein (PrP^C) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrP^C undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrP^C and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrP^C trafficking that also link intracellular and extracellular PrP^C turnover. PrP^C associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrP^C transport and facilitates lysosomal degradation over exosomal PrP^C release. Muskelin gene knockout consequently causes PrP^C 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 PrP^C turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.

Insights

Muskelin regulates cellular prion protein (PrP^C) trafficking, promoting lysosomal degradation over exosomal release. Muskelin deficiency accelerates prion disease by increasing surface PrP^C and exosome levels.

Area of Science:

Neuroscience
Cell Biology
Prion Biology

Background:

Cellular prion protein (PrP^C) is crucial for brain function but its infectious isoform causes neurodegenerative diseases like Creutzfeldt-Jakob disease.
PrP^C undergoes rapid turnover, involving plasma membrane dynamics and release via exosomes, yet its intracellular transport remains poorly understood.
Understanding PrP^C intracellular trafficking is vital for elucidating prion disease pathogenesis.

Purpose of the Study:

To identify key components regulating PrP^C intracellular transport and its link to extracellular turnover.
To investigate the role of muskelin in coordinating PrP^C trafficking and degradation pathways.
To determine the impact of altered PrP^C turnover on prion disease progression.

Main Methods:

Co-immunoprecipitation and microscopy to identify PrP^C-associated transport machinery.
Analysis of PrP^C localization and release in wild-type and muskelin knockout mice.
Assessment of prion disease onset and progression in muskelin knockout mice following prion inoculation.

Main Results:

PrP^C associates with muskelin, dynein, and KIF5C on transport vesicles, indicating their role in PrP^C trafficking.
Muskelin directs PrP^C towards lysosomal degradation, suppressing its release via exosomes.
Muskelin knockout leads to increased neuronal surface and exosomal PrP^C, accelerating prion disease onset.

Conclusions:

Muskelin acts as a critical checkpoint in cellular prion protein turnover, balancing lysosomal degradation and exosomal release.
Altered muskelin function disrupts intracellular and extracellular PrP^C trafficking, impacting neurodegenerative disease pathogenesis.
This study reveals a novel link between intracellular lysosomal pathways and extracellular exosome trafficking in prion diseases.

Read full analysis

Keywords:

degradation dynein exosome kinesin lysosome muskelin neuron prion disease recycling trafficking

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