The ubiquitin-proteasome system and learning-dependent synaptic plasticity – A 10 year update

Patrick, Morgan B.; Omar, Nour; Werner, Craig T.; Mitra, Swarup; Jarome, Timothy J.

doi:10.1016/j.neubiorev.2023.105280

Cited by 10 publications

(4 citation statements)

References 143 publications

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“…This predicts that SPAM1 may have the potential to become a potent anti-aging drug. The ubiquitin-proteasome system is involved in regulating synaptic plasticity and memory formation [37], and its dysfunction has been linked to Alzheimer's disease and dementia [38]. The PACAP/PKA pathway plays a role in tumor therapy by regulating the hedgehog signaling pathway [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…It should be mentioned that the result of the Western blot analysis showed that the effect of 0.1 µmol/kg/day SPAM1 was more significant than that of 100 µmol/kg/day SPAM1. In fact, the positive allosteric modulation site of PAC1-R may be able to detect some type of stress metabolites, such as PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), which is a natural metabolite of the stress hormone PACAP38. The working mechanism of SPAM1 involves the imitation (mimicry) of some type of stress metabolites, such as PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), to trigger self-defensive responses in the nervous system, including anti-senescence, neuroprotection, and nerve regeneration.…”

Section: Discussionmentioning

confidence: 99%

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Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

Liang,

Chen,

et al. 2024

IJMS

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Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1’s neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

Liang,

Chen,

et al. 2024

IJMS

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“…The proteomic shifts in addiction-related disorders touch upon a plethora of cellular processes, from synaptic plasticity, neuropeptide dynamics, and intracellular signaling pathways to epigenetic modulation of cocaine-responsive gene expression ( 29 ). Previous studies have implicated altered protein translation and protein degradation in addiction-related behavioral and cellular changes ( 30 – 32 ). A recent proteomic analysis in the NAc after cocaine self-administration revealed sex-specific variations, underscoring cocaine’s capacity to reconfigure proteomic profiles and modulate reward-associated behaviors ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

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“…Proteins that are unnecessary for current functions, misfolded, or damaged (due to oxidative stress, disease, or aging) must undergo degradation, with their amino acids recycled. This process is especially critical for cells with extended lifespans and intricate morphologies, such as neurons ( Hanus and Schuman, 2013 ; Morozov and Karpov, 2018 ; Patrick et al, 2023 ). Beyond the shared processes common to all cells, protein degradation serves unique functions in neurons, such as shaping synapse formation and pruning during development and regulating excitatory and inhibitory transmission in the mature brain ( Jarome and Helmstetter, 2013 ; Turker et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey

Gonzalez Ramirez,

Salvador,

Patel

et al. 2024

Front. Neuroanat.

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Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited UBE3A allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited UBE3A allele is epigenetically silenced in neurons during development by a noncoding transcript (UBE3A-ATS). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function—either by gene addition or by targeting UBE3A-ATS—are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and UBE3A-ATS biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and UBE3A-ATS expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and in situ hybridization, we mapped UBE3A and UBE3A-ATS regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal UBE3A silencing in neurons—but not glial cells—in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of UBE3A linked to AS.

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The ubiquitin-proteasome system and learning-dependent synaptic plasticity – A 10 year update

Cited by 10 publications

References 143 publications

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey

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