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Written | Qi ubiquitin proteasome system is the basic way of normal protein conversion, degradation of misfolded and pathogenic proteins, and its dysfunction has a causal relationship with many age-related pathological changes.
Due to its importance, a variety of cellular mechanisms are used to monitor the function of the proteasome and dynamically adjust its abundance, composition and activity according to homeostatic challenges.
For example, proteasome stress induces the expression of non-proteases and peptidases, which degrade peptides.
The ability to partially compensate for proteasome dysfunction.
In addition to cell-autonomous (local) responses, there is increasing evidence that stress induction in tissues or cell populations induces involuntary (systemic) adaptation of cells.
This kind of inter-organizational stress signal may help different tissues to coordinate and adapt to local and systemic challenges, so that the body can better resist and cope with steady-state disturbances.
However, it is not clear whether the proteasome stress in a tissue can be sensed by the system.
Skeletal muscle has been proven to be an important tissue regulating the aging system.
Clinical observations in humans and research on model organisms have shown that skeletal muscle affects the neurodegeneration and aging of the brain and retina.
These systemic effects may come from certain muscle secretions.
factor.
However, the mechanism of myokine and this muscle-brain signal transmission is still unknown.
Recently, the Fabio Demontis team from the St.
Jude Children’s Research Hospital in the United States published an article titled Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging in Cell Metabolism.
This study identified Stress-induced amylase and maltose mediated signal transduction from muscles to the central nervous system, maintaining protein stability in the aging brain and retina through chaperone proteins, suggesting that myogenic signals can hinder neurodegeneration in the aging process change.
First, in order to investigate whether the moderate perturbation of the proteasome in skeletal muscle induces a compensatory stress response, the authors used the UAS/Gal4 system and the skeletal muscle-specific Mhc-Gal4 driver to target Prosβ1 (20S proteasome) in the breast muscle of Drosophila.
Compared with the control group, Prosβ1RNAi can induce compensatory transcriptional changes in muscles, and also induce adaptive stress responses in distant tissues, that is, reduce proteases in head tissues.
Age-related accumulation of body substrates.
By comparing RNA-seq data, the authors found that several actins were specifically regulated by RNAi, and compared with the control group, they were continuously induced by Prosβ1RNAi and others.
Among them, the secreted amylase Amrel regulates protein quality control in a manner consistent with the up-regulation of proteasome stress transcription.
Next, the author wanted to know whether muscle-specific Amyrel RNAi would hinder the system response induced by Prosβ1RNAi.
Consistent with the hypothesis, the level of polyubiquitinated protein is higher in the insoluble part of the head of Drosophila with muscle-specific Prosβ1RNAi+AmyrelRNAi.
On the contrary, overexpression of muscle-specific Amyrel can reduce the pathogenic Huntingtin-polyQ72 aggregates that increase due to retinal aging.
These results suggest that Amyrel is a key stress-induced muscle cytokine, which can improve protein stability during aging and prevent neurodegeneration caused by disease-causing proteins.
Interestingly, the authors found that the muscle-specific Prosβ1RNAi caused higher maltose levels in the head and body of Drosophila, while glucose levels were not consistently regulated.
So is maltose a key regulator of protein quality control? The authors found that treatment with recombinant amylase and maltose can significantly reduce the accumulation of polyubiquitinated proteins under heat shock stress.
Furthermore, the authors found that RNAi targeting the maltose transmembrane transporters Slc45-1 and Slc45-2 can significantly increase Huntingtin-polyQ72 aggregates in the retina of Drosophila.
These findings indicate that the Slc45 maltose transporter is necessary for protein quality control in the central nervous system during aging.
Since Slc45-2 is highly expressed in the brain, but has little or no expression in skeletal muscle, its expression pattern may explain why protein quality control is improved in the brain, while there is no response to Amyrel in the muscle.
In addition, Slc45-2RNAi reduced the expression of key Amyrel-induced chaperone proteins (Hsp23, Hsp26, and Hsp27), indicating that Slc45-2 is necessary for the expression of Amyrel-induced target genes in the brain.
So is the above-mentioned system equally conservative among humans? Consistent with the observations in Drosophila, using siRNA of maltose transporters SLC45A3 and SLC45A4 in HEK293 cells, under heat shock conditions, polyubiquitinated proteins accumulate in insoluble components.
On this basis, the author wants to know whether maltose regulates the protein quality control and neuronal activity of human brain organoids under heat shock conditions.
On the one hand, the authors observed that maltose treatment can retain the expression of several gene clusters involved in protein quality control, such as the composition of proteasome and protease/peptidase, and CRYA (homologous to Drosophila Hsp23) has higher mRNA and protein levels.
. On the other hand, the measurement results of microelectrode arrays (MEA) show that the neuronal activity of cortical organs is not regulated by maltose at steady state, but is significantly protected by maltose at 17 hours and 43 hours after heat shock.
effect.
These findings indicate that maltose has an evolutionarily conserved role in maintaining brain protein quality control.
In general, although neurodegenerative diseases were initially regarded as a disease caused only by local changes in the brain, there is now more and more evidence that peripheral tissues contribute to the progress of this process.
This study identified the unexpected endocrine signal function of stress-induced muscle-derived Amyrel, which promotes central nervous system protein quality control through the transcriptional induction of maltose-dependent heat shock proteins in the muscle-brain stress signal transduction during aging.
effect.
Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
03.
005 Platemaker: Instructions for reprinting on the eleventh [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Due to its importance, a variety of cellular mechanisms are used to monitor the function of the proteasome and dynamically adjust its abundance, composition and activity according to homeostatic challenges.
For example, proteasome stress induces the expression of non-proteases and peptidases, which degrade peptides.
The ability to partially compensate for proteasome dysfunction.
In addition to cell-autonomous (local) responses, there is increasing evidence that stress induction in tissues or cell populations induces involuntary (systemic) adaptation of cells.
This kind of inter-organizational stress signal may help different tissues to coordinate and adapt to local and systemic challenges, so that the body can better resist and cope with steady-state disturbances.
However, it is not clear whether the proteasome stress in a tissue can be sensed by the system.
Skeletal muscle has been proven to be an important tissue regulating the aging system.
Clinical observations in humans and research on model organisms have shown that skeletal muscle affects the neurodegeneration and aging of the brain and retina.
These systemic effects may come from certain muscle secretions.
factor.
However, the mechanism of myokine and this muscle-brain signal transmission is still unknown.
Recently, the Fabio Demontis team from the St.
Jude Children’s Research Hospital in the United States published an article titled Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging in Cell Metabolism.
This study identified Stress-induced amylase and maltose mediated signal transduction from muscles to the central nervous system, maintaining protein stability in the aging brain and retina through chaperone proteins, suggesting that myogenic signals can hinder neurodegeneration in the aging process change.
First, in order to investigate whether the moderate perturbation of the proteasome in skeletal muscle induces a compensatory stress response, the authors used the UAS/Gal4 system and the skeletal muscle-specific Mhc-Gal4 driver to target Prosβ1 (20S proteasome) in the breast muscle of Drosophila.
Compared with the control group, Prosβ1RNAi can induce compensatory transcriptional changes in muscles, and also induce adaptive stress responses in distant tissues, that is, reduce proteases in head tissues.
Age-related accumulation of body substrates.
By comparing RNA-seq data, the authors found that several actins were specifically regulated by RNAi, and compared with the control group, they were continuously induced by Prosβ1RNAi and others.
Among them, the secreted amylase Amrel regulates protein quality control in a manner consistent with the up-regulation of proteasome stress transcription.
Next, the author wanted to know whether muscle-specific Amyrel RNAi would hinder the system response induced by Prosβ1RNAi.
Consistent with the hypothesis, the level of polyubiquitinated protein is higher in the insoluble part of the head of Drosophila with muscle-specific Prosβ1RNAi+AmyrelRNAi.
On the contrary, overexpression of muscle-specific Amyrel can reduce the pathogenic Huntingtin-polyQ72 aggregates that increase due to retinal aging.
These results suggest that Amyrel is a key stress-induced muscle cytokine, which can improve protein stability during aging and prevent neurodegeneration caused by disease-causing proteins.
Interestingly, the authors found that the muscle-specific Prosβ1RNAi caused higher maltose levels in the head and body of Drosophila, while glucose levels were not consistently regulated.
So is maltose a key regulator of protein quality control? The authors found that treatment with recombinant amylase and maltose can significantly reduce the accumulation of polyubiquitinated proteins under heat shock stress.
Furthermore, the authors found that RNAi targeting the maltose transmembrane transporters Slc45-1 and Slc45-2 can significantly increase Huntingtin-polyQ72 aggregates in the retina of Drosophila.
These findings indicate that the Slc45 maltose transporter is necessary for protein quality control in the central nervous system during aging.
Since Slc45-2 is highly expressed in the brain, but has little or no expression in skeletal muscle, its expression pattern may explain why protein quality control is improved in the brain, while there is no response to Amyrel in the muscle.
In addition, Slc45-2RNAi reduced the expression of key Amyrel-induced chaperone proteins (Hsp23, Hsp26, and Hsp27), indicating that Slc45-2 is necessary for the expression of Amyrel-induced target genes in the brain.
So is the above-mentioned system equally conservative among humans? Consistent with the observations in Drosophila, using siRNA of maltose transporters SLC45A3 and SLC45A4 in HEK293 cells, under heat shock conditions, polyubiquitinated proteins accumulate in insoluble components.
On this basis, the author wants to know whether maltose regulates the protein quality control and neuronal activity of human brain organoids under heat shock conditions.
On the one hand, the authors observed that maltose treatment can retain the expression of several gene clusters involved in protein quality control, such as the composition of proteasome and protease/peptidase, and CRYA (homologous to Drosophila Hsp23) has higher mRNA and protein levels.
. On the other hand, the measurement results of microelectrode arrays (MEA) show that the neuronal activity of cortical organs is not regulated by maltose at steady state, but is significantly protected by maltose at 17 hours and 43 hours after heat shock.
effect.
These findings indicate that maltose has an evolutionarily conserved role in maintaining brain protein quality control.
In general, although neurodegenerative diseases were initially regarded as a disease caused only by local changes in the brain, there is now more and more evidence that peripheral tissues contribute to the progress of this process.
This study identified the unexpected endocrine signal function of stress-induced muscle-derived Amyrel, which promotes central nervous system protein quality control through the transcriptional induction of maltose-dependent heat shock proteins in the muscle-brain stress signal transduction during aging.
effect.
Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
03.
005 Platemaker: Instructions for reprinting on the eleventh [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
