The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance, and neuronal survival in mice

Proteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradati...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-12, Vol.116 (49), p.24639-24650
Main Authors: Minis, Adi, Rodriguez, Jose A., Levin, Avi, Liu, Kai, Govek, Eve-Ellen, Hatten, Mary E., Steller, Hermann
Format: Article
Language:English
Subjects:
Adapters
Animals
Axonal transport
Axons
Axons - pathology
Axons - physiology
Behavior Observation Techniques
Biological Sciences
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell survival
Cell Survival - physiology
Central nervous system
Cerebellum
Degeneration
Degradation
Disease Models, Animal
Female
Homeostasis
Humans
Maintenance
Mice
Mice, Knockout
Motor neurons
Motor Neurons - pathology
Motor Neurons - physiology
Mouse devices
Mutation
Neurodegeneration
Neurodegenerative diseases
Neurodegenerative Diseases - diagnosis
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - pathology
Neurogenesis
Neurological complications
Neurons
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Protein biosynthesis
Protein synthesis
Proteins
Proteolysis
Proteostasis - physiology
Purkinje cells
Purkinje Cells - pathology
Purkinje Cells - physiology
Survival
Synapses - pathology
Synapses - physiology
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Summary:Proteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss, and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse central nervous system suggests a key role for PI31 in human neurodegenerative diseases.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1911921116