Key Points
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In neurons as well as other eukaryotic cells, intracellular proteins are primarily degraded by the ubiquitin–proteasome system (UPS), and membrane proteins by the lysosome system. Ubiquitylation tags proteins for proteasomal degradation and vesicular trafficking.
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Protein degradation is important for synaptic plasticity and self-renewal of neurons. The UPS can regulate presynaptic processes such as vesicle release and postsynaptic processes such as glutamate receptor turnover and postsynaptic density (PSD) reorganization.
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Many neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, are characterized by aggregates in the brain of ubiquitin-positive proteins that failed to be degraded. PARK2 (which encodes the E3 ligase parkin) mutations lead to familial Parkinson's disease, suggesting that degradative dysfunction can trigger neurodegeneration. Mutations in many UPS and lysosomal genes are now linked to neurological disorders.
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The morphology of neurons creates special demands for protein degradation with respect to membrane-protein turnover and substrate delivery to proteolytic machineries. This may explain why neurons are more susceptible to protein aggregation when protein degradation is impaired.
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Protein degradation in axons and dendrites exhibits several unique features, including long-range retrograde transport of endocytosed proteins and the translocation of proteasomes into dendritic spines.
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Various UPS components, including E3 ligases, deubiquitylating enzymes, chaperones, shuttling factors and different subtypes of proteasomes, form complex interaction networks in neurons. We know that individual components can have important functions, but detailed mechanisms remain elusive.
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Enhancing protein degradation in the brain is a potential therapeutic strategy for aggregate-related neurodegenerative disorders. Another possibility is to enhance molecular chaperones that prevent protein misfolding.
Abstract
Eukaryotic protein degradation by the proteasome and the lysosome is a dynamic and complex process in which ubiquitin has a key regulatory role. The distinctive morphology of the postmitotic neuron creates unique challenges for protein degradation systems with respect to cell-surface protein turnover and substrate delivery to proteolytic machineries that are required for both synaptic plasticity and self-renewal. Moreover, the discovery of ubiquitin-positive protein aggregates in a wide spectrum of neurodegenerative diseases underlines the importance and vulnerability of the degradative system in neurons. In this article, we discuss the molecular mechanism of protein degradation in the neuron with respect to both its function and its dysfunction.
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Acknowledgements
The authors thank C.-Y. Tai and Y. Yoon for manuscript suggestions and the support of the Howard Hughes Medical Institute.
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Glossary
- Exergonic
-
An exergonic reaction is characterized by a negative change of overall Gibbs free energy. It is thermodynamically favourable and can occur spontaneously.
- Ubiquitin
-
An 8.5 kD protein that is ubiquitously expressed in eukaryotic cells. The covalent modification of a protein by ubiquitin is called ubiquitination or ubiquitylation.
- Synaptic plasticity
-
The ability of the synaptic connection between two neurons to change in strength.
- Alzheimer's disease
-
(AD). The most common type of neurodegenerative dementia. Patients often show impairments in learning and memory. The disease's neuropathology includes neuron loss in the cerebral cortex and in some subcortical regions and the presence of aggregates in the forms of plaques (containing amyloid-β) and neurofibrillary tangles (containing hyperphosphorylated tau).
- Parkinson's disease
-
(PD). A degenerative movement disorder that causes tremor and gait disturbance. The impairment of motor skills is caused by the loss of dopaminergic neurons in the substantia nigra, where deposits of Lewy bodies are found.
- Autophagy
-
The breakdown of a cell's own components by the lysosome.
- Retrograde amnesia
-
A form of amnesia in which the subject is unable to recall events that occurred before the onset of the amnesia or before the injurious event.
- Inhibitory avoidance learning
-
In this learning paradigm, the animal prevents an aversive stimulus by suppressing a behaviour that is otherwise regularly shown in a particular environment. For instance, a rodent that received an electric foot shock for stepping off a platform learns to stay longer on the platform during test trials.
- Long-term facilitation
-
(LTF). A type of long-lasting enhancement of synaptic transmission that is induced by specific neuronal activities and that was initially described in Aplysia. A similar process called long-term potentiation was first described in the mammalian hippocampus.
- Aplysia
-
A marine snail, or sea slug, that has a simple nervous system that makes it a useful model organism for studying synaptic plasticity.
- Immediate-early gene
-
A gene that is activated transiently and rapidly in response to cellular stimuli.
- Ionotropic glutamate receptors
-
Glutamate receptors that exert their effects through the modulation of ion channel activity. In mammals they are classified into three major subtypes according to their agonist: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, NMDA (N-methyl-D-aspartate) receptors and kainate receptors.
- Postsynaptic density
-
An electron-dense structure adjacent to the postsynaptic membrane, visible in electron micrographs, that contains receptor channels, structural proteins and signal transduction proteins.
- Polyglutamine (PolyQ) expansion disease
-
Any genetic disease that results from expansions of CAG trinucleotide repeats, which are translated into lengthened polyQ regions that induce protein aggregation. Human polyQ diseases include HD, Kennedy's disease and spinocerebellar ataxias.
- Lewy bodies
-
Protein aggregates that contain α-synuclein, ubiquitin and other proteins. They were first identified in PD and were later found to be present in other neurodegenerative diseases.
- Dementia with Lewy bodies
-
(DLB). A prevalent type of late-onset dementia that is characterized by the presence of Lewy bodies distributed throughout limbic, paralimbic and neocortical regions.
- Hydra
-
Small, fresh-water predatory animals with a simple body plan and radial symmetry. Hydras are model organisms for studying regeneration and body development.
- Chaperone
-
A protein that assists the folding/unfolding and assembly/disassembly of other macromolecular structures.
- Angelman syndrome
-
A neurogenetic disease that is caused by defects in the maternal copy of UBE3A (owing to genomic imprinting, the maternal copy of UBE3A is preferentially expressed in specific brain regions). The disease is characterized by brain growth retardation and jerky movements.
- Johanson–Blizzard syndrome
-
A genetic disease that is characterized by pancreatic dysfunction, malformation and mental retardation. The disease is now linked to UBR1, which encodes an E3 ligase that selects substrates on the basis of their N-terminal residues.
- Lafora's disease
-
A fatal genetic disorder that causes seizure, myoclonus and progressive dementia. Most cases are caused by mutations in EPM2A (which encodes laforin, a protein phosphatase) or NHLRC1 (which encodes malin, an E3 ligase).
- Spinocerebellar ataxia
-
A class of genetic disorders that are characterized by slowly progressive incoordination of gait and that are often associated with poor coordination of hands, speech and eye movements.
- Multivesicular body
-
At the ultrastructural level, a structure that appears as a large vesicle that contains multiple small vesicles. It can serve as the transport intermediate between early and late endosomes.
- Degron
-
A specific part of a protein that is recognized by the degradative machinery as a proteolytic signal.
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Tai, HC., Schuman, E. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 9, 826–838 (2008). https://doi.org/10.1038/nrn2499
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DOI: https://doi.org/10.1038/nrn2499
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