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Written: Abnormal accumulation of Enzyme Protein is one of the signs of cell senescence and degradation of protein clearance.
In neurodegenerative diseases, nerve cells can be seen to accumulate large amounts of non-degradable proteins.
Degradation of proteins through lysosome autophagy is the main way for cells to eliminate abnormal proteins.
The inability of autophagy is accompanied by the progress of a variety of neurodegenerative diseases.
Chaperone mediated Autophagy (CMA) is a selective autophagy process that degrades proteins.
The molecular chaperone Hsc70 helps the target protein to unfold.
Through the receptor protein LAMP2A located on the lysosome membrane, it recognizes the exposed KFERQ group of the binding protein, and the target protein enters the lysosome for degradation.
The laboratory of Ana Maria Cuero of the Albert Einstein College of Medicine in the United States published a research paper describing the key regulatory role of CMA in the activation process of hematopoietic stem cells.
As the body's aging activity decreases, CMA can be activated by small molecule compounds to restore hematopoietic stem cell activity (see BioArt report: Nature | Chaperone-mediated autophagy: a key control element for hematopoietic stem cell activation and aging).
Recently, the Cuero laboratory, the Gavathiotis laboratory and the first Bourdenx jointly published a paper in Cell titled: Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
The author systematically explored the unique role of CMA in the maintenance of nerve cell homeostasis and neurodegenerative diseases through proteomics and other methods, which is different from general macroautophagy.
The thesis also improves CMA through small molecule compounds, which effectively delays the progression of Alzheimer's disease.
First, the author performed whole-body knockout or conditional knockout of L2A/LAMP2a expression in mice.
Both mice showed behavioral symptoms, and the symptoms of systemic knockout and conditional knockout mice were similar.
At the age of six months, lipofuscin and K63 ubiquitinated protein accumulation appeared in the excitatory neuron knockout mice, further suggesting that there is a problem with protein degradation and clearance.
Furthermore, the authors performed quantitative proteomics analysis on the insoluble component proteins of mice, and showed that a large number of insoluble proteins were accumulated in L2A knockout mice, and 75% of the proteins contained KFERQ subunits.
Proteins that are usually easy to aggregate, such as alpha-syn, tau, etc.
, show a supersaturated state and migrate to insoluble components after CMA is inhibited.
In the next step, the author compared the insoluble protein components after the inhibition of molecular chaperone autophagy (L2A) and macroautophagy (ATG7) respectively (below).
Molecular chaperone autophagy and macroautophagy affect protein series in different pathways.
For example, after CMA is blocked, material endocytosis is reduced, clathrin accumulates, and AP2 clathrin receptor is reduced; filaggrin dynamic regulation related proteins also appear to accumulate.
After molecular chaperone autophagy is inhibited, protein degradation is abnormal and neuronal function is affected.
The author speculates that in neurodegenerative diseases, the decline in CMA levels further affects the function of nerve cells and accelerates the progression of the disease.
In pathogenic hTauP301L overexpressing mice, the authors observed a decrease in the CMA activity of nerve cells.
In the Alzheimer's mouse model, further blocking of CMA speeds up the course of the disease and the accumulation of phosphorylated Tau protein appears earlier.
Proteomics analysis showed that CMA blockade caused more extensive changes in the quantity and quality of insoluble protein components.
It is conceivable that in humans, the aging process is accompanied by a decrease in CMA activity, which superimposes with other Alzheimer's diseases, and synergistically produces more serious consequences.
Finally, the author used CMA to activate the small molecule compound AR7 to treat Alzheimer's disease mice systemically, and achieved good results, showing that the increase in CMA activity is of great benefit to nerve cells.
In summary, this study shows that molecular chaperone autophagy has an important regulatory effect on nerve cell homeostasis.
Adult nerve cells rarely divide and renew, remove harmful protein accumulation in the cell, and maintain their function inseparable from the autophagy process.
The author conducted in-depth studies on conditional knockout, functional regulation and related disease models in mice, and clarified the role of molecular chaperone autophagy in the occurrence and development of neurodegenerative diseases, which has important guiding significance for future treatment and drug development.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
03.
048 Plate maker: Notes 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.
In neurodegenerative diseases, nerve cells can be seen to accumulate large amounts of non-degradable proteins.
Degradation of proteins through lysosome autophagy is the main way for cells to eliminate abnormal proteins.
The inability of autophagy is accompanied by the progress of a variety of neurodegenerative diseases.
Chaperone mediated Autophagy (CMA) is a selective autophagy process that degrades proteins.
The molecular chaperone Hsc70 helps the target protein to unfold.
Through the receptor protein LAMP2A located on the lysosome membrane, it recognizes the exposed KFERQ group of the binding protein, and the target protein enters the lysosome for degradation.
The laboratory of Ana Maria Cuero of the Albert Einstein College of Medicine in the United States published a research paper describing the key regulatory role of CMA in the activation process of hematopoietic stem cells.
As the body's aging activity decreases, CMA can be activated by small molecule compounds to restore hematopoietic stem cell activity (see BioArt report: Nature | Chaperone-mediated autophagy: a key control element for hematopoietic stem cell activation and aging).
Recently, the Cuero laboratory, the Gavathiotis laboratory and the first Bourdenx jointly published a paper in Cell titled: Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
The author systematically explored the unique role of CMA in the maintenance of nerve cell homeostasis and neurodegenerative diseases through proteomics and other methods, which is different from general macroautophagy.
The thesis also improves CMA through small molecule compounds, which effectively delays the progression of Alzheimer's disease.
First, the author performed whole-body knockout or conditional knockout of L2A/LAMP2a expression in mice.
Both mice showed behavioral symptoms, and the symptoms of systemic knockout and conditional knockout mice were similar.
At the age of six months, lipofuscin and K63 ubiquitinated protein accumulation appeared in the excitatory neuron knockout mice, further suggesting that there is a problem with protein degradation and clearance.
Furthermore, the authors performed quantitative proteomics analysis on the insoluble component proteins of mice, and showed that a large number of insoluble proteins were accumulated in L2A knockout mice, and 75% of the proteins contained KFERQ subunits.
Proteins that are usually easy to aggregate, such as alpha-syn, tau, etc.
, show a supersaturated state and migrate to insoluble components after CMA is inhibited.
In the next step, the author compared the insoluble protein components after the inhibition of molecular chaperone autophagy (L2A) and macroautophagy (ATG7) respectively (below).
Molecular chaperone autophagy and macroautophagy affect protein series in different pathways.
For example, after CMA is blocked, material endocytosis is reduced, clathrin accumulates, and AP2 clathrin receptor is reduced; filaggrin dynamic regulation related proteins also appear to accumulate.
After molecular chaperone autophagy is inhibited, protein degradation is abnormal and neuronal function is affected.
The author speculates that in neurodegenerative diseases, the decline in CMA levels further affects the function of nerve cells and accelerates the progression of the disease.
In pathogenic hTauP301L overexpressing mice, the authors observed a decrease in the CMA activity of nerve cells.
In the Alzheimer's mouse model, further blocking of CMA speeds up the course of the disease and the accumulation of phosphorylated Tau protein appears earlier.
Proteomics analysis showed that CMA blockade caused more extensive changes in the quantity and quality of insoluble protein components.
It is conceivable that in humans, the aging process is accompanied by a decrease in CMA activity, which superimposes with other Alzheimer's diseases, and synergistically produces more serious consequences.
Finally, the author used CMA to activate the small molecule compound AR7 to treat Alzheimer's disease mice systemically, and achieved good results, showing that the increase in CMA activity is of great benefit to nerve cells.
In summary, this study shows that molecular chaperone autophagy has an important regulatory effect on nerve cell homeostasis.
Adult nerve cells rarely divide and renew, remove harmful protein accumulation in the cell, and maintain their function inseparable from the autophagy process.
The author conducted in-depth studies on conditional knockout, functional regulation and related disease models in mice, and clarified the role of molecular chaperone autophagy in the occurrence and development of neurodegenerative diseases, which has important guiding significance for future treatment and drug development.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
03.
048 Plate maker: Notes 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.
