The proteasome and its role in the nervous system

Turker, Fulya; Cook, Emily K.; Margolis, Seth S.

doi:10.1016/j.chembiol.2021.04.003

Cited by 50 publications

(48 citation statements)

References 182 publications

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“…New proteins are constantly made, either constitutively or triggered by changes in activity. Here we show that in addition to the well-documented UPS and autophagic pathways for protein degradation 1,33 , and mechanisms regulating protein synthesis 66 , nascent proteins can also be immediately degraded by the ubiquitin-independent NMP pathway. This offers an additional level of regulatory vigilance over the dynamic maintenance of the fine balance needed for proteostasis in neurons, especially in face of activity fluctuations, when protein synthesis changes rapidly.…”

Section: Discussionmentioning

confidence: 77%

“…Another potential pathway through which NMPs function can affect neuronal activity is by the peptides generated by the 20S catalytic degradation of nascent protein substrates 1,23 . Our observation that inhibiting either protein synthesis or degradation in vivo both resulted in a transient increase in neuronal activity suggests that there might exist some common factors regulating neuronal activity that are generated by both protein synthesis and degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Proteostasis, the collective protein synthesis, folding and degradation mechanisms that maintain the integrity of the proteome, is pivotal for the health and normal function of the nervous system 1 . Both protein synthesis and protein degradation have been shown to be necessary for synaptic plasticity and homeostasis [2][3][4][5][6][7][8][9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

“…20S uncapped proteasomes do not require ubiquitin or ATP and have been shown to operate independently to degrade intracellular proteins, such as damaged/oxidized or unstructured proteins [18][19][20] . Emerging experimental evidence suggests a significant proportion of 20S uncapped proteasome exists in the brain and may play critical roles in neuronal physiology 1,[21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

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Neuronal membrane proteasomes homeostatically regulate neural circuit activity in vivo and are required for learning-induced behavioral plasticity

Ramachandran

McLain

et al. 2022

Preprint

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Protein degradation is critical for brain function through processes that remain poorly understood. Here we investigated the in vivo function of a recently reported neuronal membrane-associated proteasome (NMP) in the brain of Xenopus laevis tadpoles. We demonstrated that NMPs are present in the tadpole brain with biochemistry and electron microscopy, and showed that they actively degrade neuronal activity-induced nascent proteins. Using in vivo calcium imaging in the optic tectum, we showed that acute inhibition of NMP function rapidly increased spontaneous neuronal activity, resulting in hyper-synchronization among tectal neurons. At the circuit level, inhibiting NMPs abolished learning-dependent improvement in a visuomotor behavior paradigm in live animals. Our data provide the first in vivo characterization of NMP functions in the vertebrate nervous system and suggest that NMP-mediated degradation of activity-induced nascent proteins may serve as a homeostatic modulatory mechanism in neurons that is critical for regulating neuronal activity and experience-dependent circuit plasticity.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Neuronal membrane proteasomes homeostatically regulate neural circuit activity in vivo and are required for learning-induced behavioral plasticity

Ramachandran

McLain

et al. 2022

Preprint

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“…These findings raise the possibility of using LMP2 inhibitors for the treatment of Alzheimer’s disease. Based on our past experiences with site-specific proteasome inhibitors, it is highly unlikely that overall rates of protein breakdown will be reduced by selective inhibition of LMP2, suggesting that this compound will not interfere with vital proteasome function in neurons [ 126 , 127 ].…”

Section: Use Of Site-specific Immunoproteasome Inhibitors To Probe the Involvement Of These Active Sites In Autoimmunity Inflammation Andmentioning

confidence: 99%

Site-Specific Proteasome Inhibitors

Kisselev

2021

Biomolecules

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Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases.

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Person‐specific differences in ubiquitin‐proteasome mediated proteostasis in human neurons

Hsieh,

Augur,

Arbery

et al. 2024

Alzheimer's & Dementia

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BACKGROUNDImpairment of the ubiquitin‐proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment.METHODSInduced pluripotent stem cell (iPSC)‐derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation.RESULTSNeurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits.DISCUSSIONThese findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation‐prone proteins such as tau.Highlights Polygenic risk score for AD is associated with the ubiquitin‐proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation‐prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.

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The proteasome and its role in the nervous system

Cited by 50 publications

References 182 publications

Neuronal membrane proteasomes homeostatically regulate neural circuit activity in vivo and are required for learning-induced behavioral plasticity

Neuronal membrane proteasomes homeostatically regulate neural circuit activity in vivo and are required for learning-induced behavioral plasticity

Site-Specific Proteasome Inhibitors

Person‐specific differences in ubiquitin‐proteasome mediated proteostasis in human neurons

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