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Early-onset neurodegenerative disease INCL is a recessively inherited human disease.
Its pathological feature is that a large number of nerve cells die and lead to brain degeneration.
The onset of the disease is rapid.
The patient develops optic nerve degeneration at about two years of age, leading to blindness, and enters a vegetative state at about four years of age.
The life expectancy is generally not more than 14 years.
The pathogenic cause of INCL is the natural mutation of the depalmitoylation enzyme PPT1 which leads to the functional loss of the protein.
The direct result is the increase in the palmitoylation level of the related protein in the cell (the potential substrate of PPT1), which causes the change of its protein function.
At present, there is still a lack of effective treatment options in clinical practice.
Recently, the team of Xinxiang Medical College-Institute of Psychiatry and Neuromedicine Kong Eryan/Zhang Zhongjian, Liang Yinming’s team and Professor Gao Jian of Xuzhou Medical University jointly published the title "GFAP hyper-palmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice" on PNAS.
"Research papers.
The study found that the superpalmitoylation modification of the skeletal protein GFAP in astrocytes promoted the proliferation of astrocytes; PPT1, as a depalmitoylation enzyme, regulates the depalmitylation modification process of GFAP.
Therefore, in In PPT1 dysfunction mice (PPT1-KI), the level of GFAP palmitoylation is sharply increased, which leads to the activation and proliferation of astrocytes, which may aggravate the pathological process of neurodegenerative diseases.
It should be mentioned that the natural mutation (inactivation) of the Ppt1 gene in humans has caused early-onset neurodegenerative diseases (INCL).
The results of this research will provide new ideas for the diagnosis and treatment of neurodegenerative diseases such as INCL.
And new drug targets.In the central nervous system, GFAP is specifically expressed in astrocytes and belongs to the third type of intermediate filament protein, so it is usually used as a marker for astrocytes.
It is worth emphasizing that the activation of glial cells is a common pathological feature of a variety of neurological diseases (neurodegenerative diseases, stroke or traumatic brain injury, etc.
).
Studies have pointed out that the activation of astrocytes has three significant characteristics: the up-regulation of GFAP expression, the proliferation of astrocytes and the hypertrophy of cell morphology.
However, the function and potential molecular mechanism of GFAP palmitoylation modification during the activation of astrocytes have not been reported yet.
This study took GFAP palmitoylation modification as the starting point and found that changes in the level of GFAP palmitoylation modulated the proliferation rate of astrocytes.
Cytological function screening experiments found that PPT1 can effectively down-regulate the palmitoylation modification level of GFAP.
When PPT1 function is lost or knocked out, the palmitoylation modification level of GFAP rises sharply and leads to the acceleration of glial cell proliferation.
Since the dynamic protein palmitoylation modification only occurs on cysteine residues (Cysteine), further studies have found that the 291st Cysteine in GFAP is its specific palmitoylation modification site.
Based on this, the researchers hypothesized that after PPT1 is inactivated, the level of GFAP palmitoylation increases, leading to a faster proliferation rate of glial cells and activation of glial cells.
The activation of glial cells may promote the pathological process of neurodegenerative diseases.
Therefore, the author constructed GFAP palmitoylation mutant (GFAP-C291A) mice (PPT1-KI/GFAP-C291A) on the basis of PPT1-KI mice to verify the following logic: In PPT1-KI/GFAP-C291A mice, PPT1 is inactivated, and GFAP-C291A palmitoylation level cannot be upregulated, so the proliferation and activation of glial cells will be inhibited, so it may protect or delay the pathological process of neurodegenerative diseases.
Sure enough, the glial cell activation in PPT1-KI/GFAP-C291A mice was effectively inhibited, and the degenerative pathological process was significantly delayed, and the behavior and lifespan of the mice were significantly improved.
This finding means that GFAP superpalmitoylation is a key pathogenic mechanism of INCL neurodegenerative diseases, and inhibition of GFAP superpalmitoylation is beneficial to the treatment of this disease.
In summary, GFAP palmitoylation is a molecular switch that regulates the proliferation of astrocytes.
When PPT1 is inactivated or knocked out, GFAP acts as a substrate of PPT1, and its palmitoylation level is increased, which promotes Proliferation and activation of type glial cells; blocking GFAP palmitoylation modification (GFAP-C291A) can effectively inhibit the proliferation and activation of astrocytes, and more importantly, the degeneration of neurons in the brain is also Relieved.
It is reported that the reviewers and editors of the article have highly praised the findings of the study, and they believe that the results of the study may provide a new breakthrough direction for the diagnosis and treatment of related neurodegenerative diseases.
Xinxiang Medical College-Institute of Psychiatric Neuromedicine Master's degree student Yuan Wei is the first author of the paper, and Dr.
Lu Liaoxun and Professor Zhang Zhongjian from Liang Yinming's research group are the co-first authors.
Researcher Kong Eryan of Xinxiang Medical College-Institute of Psychiatry and Neuromedicine and Professor Gao Jian of Xuzhou Medical University are the co-corresponding authors.
Article link: Attached to the introduction of Kong Eryan's research group and recruitment enlightenment Kong Eryan's research group mainly uses gene knockout and knock-in mice to analyze protein palmitoyl The physiological function of chemical modification in life activities and its pathogenic mechanism in potential diseases.
After 4 years of development, the laboratory has established a multi-level technical system ranging from molecules, cells, electrophysiology to behavior, and initially established a scientific research team with strong technical characteristics and execution capabilities.
Researcher Kong Eryan completed post-doctoral training at NIH and Medical University of Vienna, and after returning to China, he joined the Xinxiang Medical College-Institute of Psychiatry and Neuromedicine.
The research direction of acylation modification and neurological diseases and malignant tumors.
The laboratory continues to recruit outstanding young researchers and backbone technicians.
Young friends with (but not limited to) neuroelectrophysiological or tumor research experience are welcome to join (ey kong@xxmu.
edu ).
Article link:
Its pathological feature is that a large number of nerve cells die and lead to brain degeneration.
The onset of the disease is rapid.
The patient develops optic nerve degeneration at about two years of age, leading to blindness, and enters a vegetative state at about four years of age.
The life expectancy is generally not more than 14 years.
The pathogenic cause of INCL is the natural mutation of the depalmitoylation enzyme PPT1 which leads to the functional loss of the protein.
The direct result is the increase in the palmitoylation level of the related protein in the cell (the potential substrate of PPT1), which causes the change of its protein function.
At present, there is still a lack of effective treatment options in clinical practice.
Recently, the team of Xinxiang Medical College-Institute of Psychiatry and Neuromedicine Kong Eryan/Zhang Zhongjian, Liang Yinming’s team and Professor Gao Jian of Xuzhou Medical University jointly published the title "GFAP hyper-palmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice" on PNAS.
"Research papers.
The study found that the superpalmitoylation modification of the skeletal protein GFAP in astrocytes promoted the proliferation of astrocytes; PPT1, as a depalmitoylation enzyme, regulates the depalmitylation modification process of GFAP.
Therefore, in In PPT1 dysfunction mice (PPT1-KI), the level of GFAP palmitoylation is sharply increased, which leads to the activation and proliferation of astrocytes, which may aggravate the pathological process of neurodegenerative diseases.
It should be mentioned that the natural mutation (inactivation) of the Ppt1 gene in humans has caused early-onset neurodegenerative diseases (INCL).
The results of this research will provide new ideas for the diagnosis and treatment of neurodegenerative diseases such as INCL.
And new drug targets.In the central nervous system, GFAP is specifically expressed in astrocytes and belongs to the third type of intermediate filament protein, so it is usually used as a marker for astrocytes.
It is worth emphasizing that the activation of glial cells is a common pathological feature of a variety of neurological diseases (neurodegenerative diseases, stroke or traumatic brain injury, etc.
).
Studies have pointed out that the activation of astrocytes has three significant characteristics: the up-regulation of GFAP expression, the proliferation of astrocytes and the hypertrophy of cell morphology.
However, the function and potential molecular mechanism of GFAP palmitoylation modification during the activation of astrocytes have not been reported yet.
This study took GFAP palmitoylation modification as the starting point and found that changes in the level of GFAP palmitoylation modulated the proliferation rate of astrocytes.
Cytological function screening experiments found that PPT1 can effectively down-regulate the palmitoylation modification level of GFAP.
When PPT1 function is lost or knocked out, the palmitoylation modification level of GFAP rises sharply and leads to the acceleration of glial cell proliferation.
Since the dynamic protein palmitoylation modification only occurs on cysteine residues (Cysteine), further studies have found that the 291st Cysteine in GFAP is its specific palmitoylation modification site.
Based on this, the researchers hypothesized that after PPT1 is inactivated, the level of GFAP palmitoylation increases, leading to a faster proliferation rate of glial cells and activation of glial cells.
The activation of glial cells may promote the pathological process of neurodegenerative diseases.
Therefore, the author constructed GFAP palmitoylation mutant (GFAP-C291A) mice (PPT1-KI/GFAP-C291A) on the basis of PPT1-KI mice to verify the following logic: In PPT1-KI/GFAP-C291A mice, PPT1 is inactivated, and GFAP-C291A palmitoylation level cannot be upregulated, so the proliferation and activation of glial cells will be inhibited, so it may protect or delay the pathological process of neurodegenerative diseases.
Sure enough, the glial cell activation in PPT1-KI/GFAP-C291A mice was effectively inhibited, and the degenerative pathological process was significantly delayed, and the behavior and lifespan of the mice were significantly improved.
This finding means that GFAP superpalmitoylation is a key pathogenic mechanism of INCL neurodegenerative diseases, and inhibition of GFAP superpalmitoylation is beneficial to the treatment of this disease.
In summary, GFAP palmitoylation is a molecular switch that regulates the proliferation of astrocytes.
When PPT1 is inactivated or knocked out, GFAP acts as a substrate of PPT1, and its palmitoylation level is increased, which promotes Proliferation and activation of type glial cells; blocking GFAP palmitoylation modification (GFAP-C291A) can effectively inhibit the proliferation and activation of astrocytes, and more importantly, the degeneration of neurons in the brain is also Relieved.
It is reported that the reviewers and editors of the article have highly praised the findings of the study, and they believe that the results of the study may provide a new breakthrough direction for the diagnosis and treatment of related neurodegenerative diseases.
Xinxiang Medical College-Institute of Psychiatric Neuromedicine Master's degree student Yuan Wei is the first author of the paper, and Dr.
Lu Liaoxun and Professor Zhang Zhongjian from Liang Yinming's research group are the co-first authors.
Researcher Kong Eryan of Xinxiang Medical College-Institute of Psychiatry and Neuromedicine and Professor Gao Jian of Xuzhou Medical University are the co-corresponding authors.
Article link: Attached to the introduction of Kong Eryan's research group and recruitment enlightenment Kong Eryan's research group mainly uses gene knockout and knock-in mice to analyze protein palmitoyl The physiological function of chemical modification in life activities and its pathogenic mechanism in potential diseases.
After 4 years of development, the laboratory has established a multi-level technical system ranging from molecules, cells, electrophysiology to behavior, and initially established a scientific research team with strong technical characteristics and execution capabilities.
Researcher Kong Eryan completed post-doctoral training at NIH and Medical University of Vienna, and after returning to China, he joined the Xinxiang Medical College-Institute of Psychiatry and Neuromedicine.
The research direction of acylation modification and neurological diseases and malignant tumors.
The laboratory continues to recruit outstanding young researchers and backbone technicians.
Young friends with (but not limited to) neuroelectrophysiological or tumor research experience are welcome to join (ey kong@xxmu.
edu ).
Article link:
