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Viral Tracing of Genetically Defined Neural Circuitry
Published on: October 17, 2012
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VCP suppresses proteopathic seeding in neurons.
Jiang Zhu1, Sara Pittman1, Dhruva Dhavale1
1Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO, 63110, USA.
Molecular Neurodegeneration
|April 13, 2022
Summary
Valosin Containing Protein (VCP) suppresses the seeding of alpha-synuclein (αS) and TDP-43 aggregates, crucial in neurodegeneration. VCP dysfunction exacerbates protein seeding, highlighting its role in preventing proteopathic spread.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Proteopathic seeds like alpha-synuclein (αS), Tau, and TDP-43 spread in the brain, causing neurodegeneration.
- Multisystem proteinopathy (MSP) is linked to Valosin Containing Protein (VCP) mutations, leading to muscle and neuronal damage with protein aggregates.
- The cellular mechanisms governing proteopathic seed spread are not fully understood.
Purpose of the Study:
- To identify cellular machinery involved in the spread of proteopathic seeds.
- To investigate the role of Valosin Containing Protein (VCP) in the seeding and spread of αS and TDP-43.
Main Methods:
- Genome-wide CRISPR-Cas9 screen using αS biosensors.
- Assessed αS and TDP-43 seeding activity in FRET/Flow biosensor cells and primary neurons.
- Analyzed in vivo seeding by immunostaining in mice carrying VCP mutations.
Main Results:
- Identified 154 genes suppressing αS seeding; VCP was a key suppressor.
- VCP inhibition or MSP-VCP mutation increased αS and TDP-43 seeding in cells and neurons.
- VCP-MSP mutation carrying mice showed increased phospho αS after αS seeding.
Conclusions:
- Valosin Containing Protein (VCP) acts as a suppressor of αS and TDP-43 aggregate seeding.
- VCP's role in lysosome clearance (lysophagy) may prevent proteopathic spread.
- VCP dysfunction could explain diverse pathologies in VCP-associated MSP.
