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And use rigorous academic and logical thinking to explore the mysteries of neuroscience.
Written by Zheng Ruimao, edited by Wang Sizhen.
Parkinson's disease (PD) is a common degenerative disease of the nervous system, which occurs frequently in the elderly.
The prevalence of PD in people over 65 years of age in my country is about 1.
7% [1].
In recent years, the incidence of PD has been significantly increasing, and it is estimated that there will be 140 million PD patients by 2040 [2].
It is worth noting that most PD patients are sporadic cases, and less than 10% of patients have a family genetic history.
The main pathological change of PD is the degeneration and death of dopaminergic neurons in the substantia nigra region, which leads to the decrease of dopamine content in the striatum (striatum), which is the center of brain movement control, and causes striae.
The dysfunction of body movement control, its clinical manifestations are mainly static tremor, bradykinesia, muscle rigidity and postural and gait disorders [3-4].
At present, it is believed that the onset of PD is related to environmental factors, oxidative stress, genetic factors, aging, protein homeostasis imbalance, and metabolic homeostasis imbalance.
Because its pathogenic mechanism is still unclear, there is a lack of effective treatment for the cause.
drug.
On March 24, 2021, the team of researcher Zheng Ruimao from Peking University School of Basic Medicine published a research paper entitled The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson's disease online in Cell Death and Differentiation.
The anti-Parkinsonian pharmacological action mechanism of natural drug compounds with the therapeutic potential of Parkinson's disease, and a new pathogenesis of Parkinson's disease is proposed.The oxidative stress of dopaminergic neurons in the substantia nigra of the midbrain and apoptosis caused by neuroinflammation are considered to be important molecular mechanisms of PD.
Withaferin A, whose Chinese name is Ashwagandha A, is a steroidal ester isolated from Ashwagandha [5].
As a natural drug compound that can penetrate the blood-brain barrier, buburnin A has significant antioxidant and anti-inflammatory functions [5].
So does bucarne A have a neuroprotective effect on PD? The research team found that for traditional PD model mice (MPTP) and humanized PD model mice (AAV-human-αsyn), solanine A can support the ability of neurons in the substantia nigra of these mice to synthesize dopamine and slow down The Parkinson-like damage of these neurons, that is to say, ashgarin A can alleviate the symptoms of PD and play a neuroprotective effect.
Fudnerin A may be a potential drug for the treatment of PD.
Therefore, the author conducted an in-depth study.
The results of mouse model transcriptome sequencing and bioinformatics analysis showed significant changes in the neuronal genes of the substantia nigra region of mice under the action of the compound.
At the same time, the substantia nigra transcriptome sequencing database and meta-analysis of human PD patients The genes that showed significant changes in the nerve cells in the substantia nigra of human PD patients, and then through a comparative analysis of the PD-related genes of the two (human and mouse), a series of genetically engineered mice and related experiments, the researchers determined DJ-1 , NRF2 and STING are most likely to be the target molecules of buburnin A to play a neuroprotective effect (ie, anti-Parkinson) in PD.
DJ-1 is a gene related to the pathogenesis of PD [6]; NRF2 is a key antioxidant factor [7]; STING is an immune-related molecule that can be activated by fragmented endogenous or exogenous DNA and trigger neuroinflammation [8].
Therefore, the researchers conducted transcriptome sequencing and bio-information analysis of current clinically used anti-Parkinson drugs, such as amantadine (amantadine) [9], and azalea, and the results showed that for the nerves in the substantia nigra Cells, these drugs may alleviate the apoptosis of dopamine neurons through their significant antioxidant and anti-neuro-inflammatory effects.
The results also show that the DJ1-NRF2-STING signaling pathway mediates the anti-Parkinson effect of ashwagandin A. This human-oriented research also provides new reference information for the development of anti-Parkinson drugs.
The DJ1-NRF2-STING signaling pathway mediates the anti-Parkinson effect of Withaferin A (picture quoted from: Zhao, M.
, et al.
Cell Death Differ (2021)) Conclusion and discussion of the article It is worth noting that the study proposes a PD The new theory of pathogenesis: the neuroinflammation caused by exogenous or endogenous fragmented DNA activating the STING system may be a potential factor leading to dopamine neuron apoptosis and then triggering PD.
The study puts forward a new pathogenesis of PD: virus infection and damaged mitochondria can release fragmented DNA fragments to activate STING to trigger neuroinflammation, which leads to apoptosis of substantia nigra dopamine neurons, which may lead to the pathogenesis of PD.
Studies have also pointed out: Amantadine is a commonly used antiviral drug [9], but it is also used in the clinical treatment of PD, although its anti-Parkinson’s disease mechanism has not been clear; and studies believe that amantadine is anti-Parkinson’s The mechanism is likely to slow down apoptosis induced by neuroinflammation by acting on STING.
Article summary picture: STING-mediated neuroinflammation-induced apoptosis may be a new mechanism of Parkinson's pathogenesis (picture quoted from: Zhao, M.
, et al.
Cell Death Differ (2021)) Zhao Miao (third from right), Wang Bingwei ( First from left), Zhijie Su (third from left), and Ruimao Zheng (first from right) (picture source: Zheng Ruimao laboratory) Dr.
Zhao Miao from Peking University School of Basic Medicine is the first author of the paper, and researcher Zheng Ruimao is the corresponding author.
The research was completed on the platforms of the Department of Human Anatomy, Histology and Embryology, the Institute of Neuroscience of Peking University, the Key Laboratory of Neuroscience of the Ministry of Education, and the Key Laboratory of Neuroscience of the National Health Commission.
Research and development plan and the support of the National Natural Science Foundation of China. Original link: Recommended high-quality scientific research training courses [1] Patch clamp and optogenetics and calcium imaging technology seminar (27-28 February 21 ) (April-May 2020 courses can be booked) [2] Online︱Single-cell sequencing data analysis and research thinking seminar (January 16-17, 21) (April-May 2021 courses can be booked) References (slide up and down to view) [1] Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D.
A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease.
Sci Transl Med.
2019;11:eaau6870.
[2] Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P.
Triggers, facilitators, and aggravators: redefining Parkinson's disease pathogenesis.
Trends Neurosci.
2019;42:4–13.
[3] Koprich JB, Kalia LV, Brotchie JM.
Animal models of alphasynucleinopathy for Parkinson disease drug development.
Nat Rev Neurosci.
2017;18:515–529.
[4] Charvin D, Medori R, Hauser RA, Rascol O.
Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.
Nat Rev Drug Disco.
2018;17:844.
[5] Swarup V, Phaneuf D, Dupre N, Petri S, Strong M, Kriz J, et al.
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways.
J Exp Med.
2011;208:2429–2447 [6] Piston D, Alvarez-Erviti L, Bansal V, Gargano D, Yao Z, Szabadkai G, et al.
DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis.
Hum Mol Genet.
2018;27:576.
【7】Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, Leon R.
Nrf2-ARE pathway: An emerging target against oxidative stressand neuroinflammation in neurodegenerative diseases.
PharmTher.
2016;157:84–104.
[8] Nazmi A, Field RH, Griffin EW, Haugh O, Hennessy E, Cox D, et al.
Chronic neurodegeneration induces type I interferon synthesis via STING,shaping microglial phenotype and accelerating disease progression.
Glia.
2019;67:1254–1276.
[9] Hubsher G, Haider M, Okun MS.
Amantadine: the journey from fighting flu to treating Parkinson disease.
Neurology.
2012;78: 1096– 1099.
Plate Making︱Wang Sizhen End of this article
Written by Zheng Ruimao, edited by Wang Sizhen.
Parkinson's disease (PD) is a common degenerative disease of the nervous system, which occurs frequently in the elderly.
The prevalence of PD in people over 65 years of age in my country is about 1.
7% [1].
In recent years, the incidence of PD has been significantly increasing, and it is estimated that there will be 140 million PD patients by 2040 [2].
It is worth noting that most PD patients are sporadic cases, and less than 10% of patients have a family genetic history.
The main pathological change of PD is the degeneration and death of dopaminergic neurons in the substantia nigra region, which leads to the decrease of dopamine content in the striatum (striatum), which is the center of brain movement control, and causes striae.
The dysfunction of body movement control, its clinical manifestations are mainly static tremor, bradykinesia, muscle rigidity and postural and gait disorders [3-4].
At present, it is believed that the onset of PD is related to environmental factors, oxidative stress, genetic factors, aging, protein homeostasis imbalance, and metabolic homeostasis imbalance.
Because its pathogenic mechanism is still unclear, there is a lack of effective treatment for the cause.
drug.
On March 24, 2021, the team of researcher Zheng Ruimao from Peking University School of Basic Medicine published a research paper entitled The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson's disease online in Cell Death and Differentiation.
The anti-Parkinsonian pharmacological action mechanism of natural drug compounds with the therapeutic potential of Parkinson's disease, and a new pathogenesis of Parkinson's disease is proposed.The oxidative stress of dopaminergic neurons in the substantia nigra of the midbrain and apoptosis caused by neuroinflammation are considered to be important molecular mechanisms of PD.
Withaferin A, whose Chinese name is Ashwagandha A, is a steroidal ester isolated from Ashwagandha [5].
As a natural drug compound that can penetrate the blood-brain barrier, buburnin A has significant antioxidant and anti-inflammatory functions [5].
So does bucarne A have a neuroprotective effect on PD? The research team found that for traditional PD model mice (MPTP) and humanized PD model mice (AAV-human-αsyn), solanine A can support the ability of neurons in the substantia nigra of these mice to synthesize dopamine and slow down The Parkinson-like damage of these neurons, that is to say, ashgarin A can alleviate the symptoms of PD and play a neuroprotective effect.
Fudnerin A may be a potential drug for the treatment of PD.
Therefore, the author conducted an in-depth study.
The results of mouse model transcriptome sequencing and bioinformatics analysis showed significant changes in the neuronal genes of the substantia nigra region of mice under the action of the compound.
At the same time, the substantia nigra transcriptome sequencing database and meta-analysis of human PD patients The genes that showed significant changes in the nerve cells in the substantia nigra of human PD patients, and then through a comparative analysis of the PD-related genes of the two (human and mouse), a series of genetically engineered mice and related experiments, the researchers determined DJ-1 , NRF2 and STING are most likely to be the target molecules of buburnin A to play a neuroprotective effect (ie, anti-Parkinson) in PD.
DJ-1 is a gene related to the pathogenesis of PD [6]; NRF2 is a key antioxidant factor [7]; STING is an immune-related molecule that can be activated by fragmented endogenous or exogenous DNA and trigger neuroinflammation [8].
Therefore, the researchers conducted transcriptome sequencing and bio-information analysis of current clinically used anti-Parkinson drugs, such as amantadine (amantadine) [9], and azalea, and the results showed that for the nerves in the substantia nigra Cells, these drugs may alleviate the apoptosis of dopamine neurons through their significant antioxidant and anti-neuro-inflammatory effects.
The results also show that the DJ1-NRF2-STING signaling pathway mediates the anti-Parkinson effect of ashwagandin A. This human-oriented research also provides new reference information for the development of anti-Parkinson drugs.
The DJ1-NRF2-STING signaling pathway mediates the anti-Parkinson effect of Withaferin A (picture quoted from: Zhao, M.
, et al.
Cell Death Differ (2021)) Conclusion and discussion of the article It is worth noting that the study proposes a PD The new theory of pathogenesis: the neuroinflammation caused by exogenous or endogenous fragmented DNA activating the STING system may be a potential factor leading to dopamine neuron apoptosis and then triggering PD.
The study puts forward a new pathogenesis of PD: virus infection and damaged mitochondria can release fragmented DNA fragments to activate STING to trigger neuroinflammation, which leads to apoptosis of substantia nigra dopamine neurons, which may lead to the pathogenesis of PD.
Studies have also pointed out: Amantadine is a commonly used antiviral drug [9], but it is also used in the clinical treatment of PD, although its anti-Parkinson’s disease mechanism has not been clear; and studies believe that amantadine is anti-Parkinson’s The mechanism is likely to slow down apoptosis induced by neuroinflammation by acting on STING.
Article summary picture: STING-mediated neuroinflammation-induced apoptosis may be a new mechanism of Parkinson's pathogenesis (picture quoted from: Zhao, M.
, et al.
Cell Death Differ (2021)) Zhao Miao (third from right), Wang Bingwei ( First from left), Zhijie Su (third from left), and Ruimao Zheng (first from right) (picture source: Zheng Ruimao laboratory) Dr.
Zhao Miao from Peking University School of Basic Medicine is the first author of the paper, and researcher Zheng Ruimao is the corresponding author.
The research was completed on the platforms of the Department of Human Anatomy, Histology and Embryology, the Institute of Neuroscience of Peking University, the Key Laboratory of Neuroscience of the Ministry of Education, and the Key Laboratory of Neuroscience of the National Health Commission.
Research and development plan and the support of the National Natural Science Foundation of China. Original link: Recommended high-quality scientific research training courses [1] Patch clamp and optogenetics and calcium imaging technology seminar (27-28 February 21 ) (April-May 2020 courses can be booked) [2] Online︱Single-cell sequencing data analysis and research thinking seminar (January 16-17, 21) (April-May 2021 courses can be booked) References (slide up and down to view) [1] Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D.
A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease.
Sci Transl Med.
2019;11:eaau6870.
[2] Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P.
Triggers, facilitators, and aggravators: redefining Parkinson's disease pathogenesis.
Trends Neurosci.
2019;42:4–13.
[3] Koprich JB, Kalia LV, Brotchie JM.
Animal models of alphasynucleinopathy for Parkinson disease drug development.
Nat Rev Neurosci.
2017;18:515–529.
[4] Charvin D, Medori R, Hauser RA, Rascol O.
Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.
Nat Rev Drug Disco.
2018;17:844.
[5] Swarup V, Phaneuf D, Dupre N, Petri S, Strong M, Kriz J, et al.
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways.
J Exp Med.
2011;208:2429–2447 [6] Piston D, Alvarez-Erviti L, Bansal V, Gargano D, Yao Z, Szabadkai G, et al.
DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis.
Hum Mol Genet.
2018;27:576.
【7】Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, Leon R.
Nrf2-ARE pathway: An emerging target against oxidative stressand neuroinflammation in neurodegenerative diseases.
PharmTher.
2016;157:84–104.
[8] Nazmi A, Field RH, Griffin EW, Haugh O, Hennessy E, Cox D, et al.
Chronic neurodegeneration induces type I interferon synthesis via STING,shaping microglial phenotype and accelerating disease progression.
Glia.
2019;67:1254–1276.
[9] Hubsher G, Haider M, Okun MS.
Amantadine: the journey from fighting flu to treating Parkinson disease.
Neurology.
2012;78: 1096– 1099.
Plate Making︱Wang Sizhen End of this article
