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Proteasome anchors to neuronal membranes to become a signaling platform: moonlightner or hidden deceiver?

Within the nervous system, the proteasome system (PROS) has been reported to be involved in a number of cellular processes. Furthermore, PROS appears to modulate the differentiation of different cell types of the nervous system and is also involved in that of motor neurons. Inhibition of the UBA1 enzyme results in decreased motor neuron viability and neurite growth, and proteasome inhibition appears to be necessary for oligodendrocyte differentiation. PROS components have also been shown to be necessary for axon growth and guidance during development in several animal models. Synaptic plasticity is another phenomenon closely related to the function of the PROS. First, studies have reported that the protein kinase CaMKII enhances proteasome migration to dendritic spines following synaptic stimulation with the glutamatergic receptor.

After proteasome migration, CaMKII phosphorylates the proteasome subunit Rpt-6, enhancing the growth of dendritic spines. Furthermore, PROS is also believed to participate in long-term potentiation (LTP), as evidence suggests that proteasome inhibition upregulates early-phase LTP and facilitates the induction of late-phase LTP; however, it also disrupts the maintenance and stability of late-phase LTP. The proteasome has also been proposed to play an important role during neurogenesis, as gankyrin, a proteasomal assembly chaperone, has been shown to enhance neurogenesis in neural stem cells while inhibition of PROS activity decreases their proliferation. Interactions of the proteasome with some intracellular signaling pathways have been demonstrated. In addition to the aforementioned CAMKII, the protein kinases PKA and PKC can also regulate PROS.

The endocannabinoid system is critical for the normal function and development of the nervous system. Cellular differentiation of the nervous system and the construction of neural circuits are also partially regulated by endocannabinoids. Several cannabinoid receptors regulate neurogenesis in the adult brain. CB1R and TRPV1 are believed to promote neuronal differentiation in the subventricular zone and dentate gyrus. Furthermore, other cell culture studies have shown that proliferation of cells in the dentate gyrus requires costimulation of CB1R and CB2R, while proliferation in the subventricular zone is stimulated by CB1R or CB2R, separately. Other cannabinoid receptors that stimulate hippocampal neurogenesis are GPR55. Therefore the possibility that the proteasome can remodel nerve cells following stimulation via receptors is an established biological reality.

However, endocannabinoids can also control pain phenomena and apparently itching. Now, researchers at Johns Hopkins Medicine, studying nerve cells grown in the lab and in mice, say the proteasome’s role may go much further. Its additional role could shift from waste sorter to signal messenger in dorsal root ganglion neurons, cells that transmit sensory signals from nerve cells near the skin to the brain. The results of their experiments show that proteasomes can help specialized neurons sense their surroundings, send signals to each other, and potentially distinguish between the perception of pain and itch, a finding that could help scientists to better understand these sensory processes and new targets for the treatment of pain and other sensory disorders.

Seth S. Margolis, PhD, associate professor of biological chemistry at the Johns Hopkins University School of Medicine, and his team first discovered proteasomes in the plasma membranes of central nervous system neurons in mice in 2017, which they dubbed proteasomes of the neuronal membrane (NMP), and continued to study how these special proteasomes promote messaging or crosstalk between neurons. Drs Margolis and Landeros wondered whether proteasomes could be found in peripheral neurons and, if so, what they might do. Using mouse antibodies that attach to proteasomes and other methods, the researchers found proteasomes on the surface of neurons in the spinal cord, dorsal root ganglia, sciatic nerve, and peripheral nerves that innervate the skin. The researchers were also able to find proteasomes in the same type of peripheral neurons grown in laboratory culture dishes.

To understand proteasome function in peripheral sensory neurons, the researchers gave mice biotin-epoxomicin, a cell membrane-impermeable proteasome inhibitor that blocks the function of neuronal membrane proteasomes. Then, they performed classic sensory tests. The researchers found that mice injected with biotin-epoxomicin on one side of the body were 25% to 50% slower than the other side in responding to sensory tests. This suggests that membrane proteasomes are important for sensation and must facilitate it at the signaling level. The researchers used single-cell sequencing technology to determine that membrane proteasomes were expressed in a subpopulation of neurons involved in itch sensation and known to be sensitive to histamine, which everyone knows to cause itch in allergy and allergic reactions like eczema or other skin rashes.

In laboratory culture dishes, the researchers stimulated both itch-related and non-itch-related neurons and blocked their membrane proteasomes with biotin-epoxomicin. This resulted in changes to activity in all cells. Inhibition of this neuronal membrane-localized proteasome in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in calcium signaling induced by depolarization with potassium chloride or histamine. Proteasome blocking appears to have an activity-modulating effect on all cells, despite being expressed in a subpopulation, suggesting that proteasomes facilitate some sort of cross-talk between these cells. This discovery is astonishing, since the proteasome has always been associated with internal cellular phenomena such as the cell cycle and also the processing of antigens by immune cells. Its blockade is useful even to cure some human cancers.

A similar research published a few months ago has added further interest to this information: certain protein fragments (peptides) produced by NMP activity are released by neuronal cells and can interact with external receptors to trigger signals through NMDAR-type glutamate receptors but not AMPA. This difference is important, because the NMDA receptor is essentially a calcium channel that allows the influx of this ion from outside the cell. Instead, AMPA receptors act through G proteins, as do other hormone receptors. The influx of calcium mediated by the NMDA receptor is coupled to the activation of the protein kinases CAMKII and PKC, which will serve the cell to activate the nuclear transcription factor CREB necessary to express memory genes (Fos, Egr4, Npas4, etc.) and other processes of cellular remodeling or differentiation.

So it is possible that proteasome and other known signaling complexes still have an ace up their sleeve to reveal and we don’t know about it.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Landeros EV et al. Cell Reports 2024 Apr 8:115048.

Türker F et al. Mol Biol Cell. 2024 Jan 1; 35(1):ar6.

Atta H, Alzahaby N et al. Bioorg Chem. 2023; 133:106427.

Patrick MB et al. Neurosci Biobehav Rev. 2023; 152:105280.

Sun C, Desch K et al. Science. 2023; 380(6647):eadf2018.

Sahu I, Glickman MH. Biomolecules. 2021; 11(2):148.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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