CN112587664A - Use of inhibitors of long chain acyl-coa synthetase 4 for the treatment of parkinson's disease - Google Patents
Use of inhibitors of long chain acyl-coa synthetase 4 for the treatment of parkinson's disease Download PDFInfo
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Abstract
The invention discloses application of an inhibitor of long-chain fatty acyl-CoA synthetase 4 in treating Parkinson's disease, and relates to the technical field of Parkinson's disease treatment. The invention discloses application of an inhibitor of long-chain acyl-coenzyme A synthetase 4 in preparing a medicament for preventing or treating Parkinson's disease. The research of the invention discovers that the inhibitor of ACSL4 can improve the relevant symptoms of the Parkinson's disease by taking long-chain acyl-coenzyme A synthetase 4(ACSL4) as a target point, and has a therapeutic effect on the Parkinson's disease; the invention provides a new target and a new strategy for treating the Parkinson's disease.
Description
Technical Field
The invention relates to the technical field of Parkinson disease treatment, in particular to application of an inhibitor of long-chain acyl-CoA synthetase 4 in treating Parkinson disease.
Background
Parkinson's Disease (PD) is a neurodegenerative disease that occurs well in the elderly, and is mainly caused by the loss of brain cells that can produce dopamine. The clinical features are that the dyskinesia includes progressive bradykinesia, muscular rigidity, resting tremor, abnormal gait of posture and the like, and in addition, the dyskinesia can be accompanied by a large number of non-motor symptoms (NMS), such as hyposmia, constipation, depression, sleep disorder and the like. With the progress of the disease course, the motor symptoms and non-motor symptoms gradually get worse, and motor complications including the decline of the curative effect of the medicine, the phenomenon of "on/off", and dyskinesia appear in the later stage of the disease. Patients in later stage of diseases often have incapability of self-care in life due to balance disorder, falling, gait freezing, dysphagia, language disorder and the like, even lie in bed for a long time, and the life quality is seriously reduced.
According to statistics, nearly 300 million Parkinson disease patients in China account for half of the Parkinson disease patients all over the world, and are the most sick countries in the world. And about 10 ten thousand patients are newly added every year, the incidence rate is 1.7 percent above 65 years old, the diagnosis rate only accounts for four percent, and less than 50 ten thousand patients with the Parkinson disease can be truly diagnosed and treated in 300 ten thousand patients with the Parkinson disease due to missed diagnosis, misdiagnosis and the like. Statistics show that the number of parkinson patients worldwide has doubled, over 620 million, from 1990 to 2015. Experts predict that by 2040 this number will reach 1200 ten thousand. Parkinson's disease imposes a tremendous economic burden on society, and the direct or indirect directions of expenditure mainly include: disease treatment costs, social insurance costs, lost income due to incapacity, etc., these patients in the united states alone will cost up to 2500 million dollars per year.
Disclosure of Invention
The invention aims to provide an application of an inhibitor of long-chain acyl-CoA synthetase 4 in treating Parkinson's disease. The research of the invention discovers that the inhibitor of ACSL4 can improve the relevant symptoms of the Parkinson's disease by taking long-chain acyl-coenzyme A synthetase 4(ACSL4) as a target point, and has a therapeutic effect on the Parkinson's disease; the invention provides a new target and a new strategy for treating the Parkinson's disease.
The invention is realized by the following steps:
in one aspect, the invention provides the use of an inhibitor of long chain acyl-coa synthetase 4 in the manufacture of a medicament for the prevention or treatment of parkinson's disease.
The implementation of the invention discovers that the expression vector is obtained by carrying out genome-wide transcriptome analysis on substantia nigra pars compacta (SNpc) neurons separated from serum and brain tissues of a Parkinson disease patient: SNpc neurons in brain tissue and serum ACSL4 transcript levels were significantly up-regulated in Parkinson's disease patients. Through further experiments, the expression and activity of the ACSL4 are inhibited, so that the motor symptoms of the mouse model of the Parkinson disease can be obviously improved, and the death of SN neurons of the mouse model of the Parkinson disease can be saved. Thus indicating that the ACSL4 is a potential target point for treating the Parkinson's disease. The improvement effect on the treatment of the Parkinson's disease can be realized by inhibiting the ACSL4, such as inhibiting the expression of the ACSL4 or the coding gene thereof in the patient, or inhibiting the biological activity of the ACSL4 in the patient, so that the dyskinesia of the patient can be at least relieved, the reduction of tyrosine hydroxylase can be reduced, and the death of dopamine neurons can be reduced.
Based on the above, the present invention provides an inhibitor of long-chain acyl-coa synthetase 4, which has an effect of treating parkinson's disease as a drug for preventing or treating parkinson's disease.
The invention discloses the key role of the ACSL4 in the dyskinesia and occurrence and development of the Parkinson disease, provides a brand-new theory and strategy for the research and treatment of the Parkinson disease, and lays a foundation for the development of relevant treatment medicines for the Parkinson disease.
Alternatively, in some embodiments of the invention, the inhibitor is selected from any one of triacin C and pioglitazone.
Based on the present disclosure, one skilled in the art can select suitable long-chain acyl-coa synthetase 4 inhibitors for the treatment of parkinson's disease, including but not limited to triacin C and pioglitazone as described above. The invention belongs to the protection scope of the invention as long as the substance which takes the long-chain acyl-coenzyme A synthetase 4 as the target spot to inhibit the activity is adopted as the medicine for treating the Parkinson disease.
Alternatively, in some embodiments of the invention, the inhibitor is a viral vector that inhibits the expression of long chain acyl-coa synthetase 4.
Based on the present disclosure, one skilled in the art can also use gene therapy techniques, such as introduction into a patient using a suitable viral vector to achieve treatment of Parkinson's disease, provided that the viral vector is capable of inhibiting the expression of long-chain acyl-CoA synthetase 4, such as inhibiting the gene expression thereof, to reduce the level of long-chain acyl-CoA synthetase 4, thereby achieving the therapeutic effect of Parkinson's disease.
Optionally, in some embodiments of the invention, the viral vector is an adeno-associated viral vector.
Alternatively, in some embodiments of the invention, the adeno-associated viral vector is an AAV8 viral vector.
In other embodiments, the adeno-associated virus vector can also be selected from AAV1, AAV2, AAV5, AAV6, AAV7, or AAV9, and one skilled in the art can select a suitable type of virus vector as desired.
It should be noted that, under the condition that the long-chain acyl-CoA synthetase 4 and the gene sequence thereof are known, the related viral vector for inhibiting the expression of ACSL4 gene can be easily prepared by the skilled person through the routine technology in the field.
In addition, the skilled person can also use RNA interference technology to inhibit the expression of ACSL4 gene in the patient at the transcription level, therefore, it also falls into the protection scope of the present invention to use the related product which aims at inhibiting ACSL4 gene and is suitable for RNA interference technology as the drug for treating Parkinson's disease.
Optionally, in some embodiments of the invention, the pharmaceutical formulation is an injection.
The skilled person can treat Parkinson's disease by using a suitable dosage form for the above inhibitor according to needs, including but not limited to injection, and no creative work is required for the skilled person in any dosage form, so that the use of any dosage form of the above inhibitor for treating Parkinson's disease is within the protection scope of the present invention.
In another aspect, the present invention provides a medicament for preventing or treating parkinson's disease, which targets long-chain acyl-coa synthetase 4 or a gene encoding the same, and inhibits the activity or expression level of long-chain acyl-coa synthetase 4.
Based on the results of the present study, one skilled in the art can easily think of treating Parkinson's disease by using long-chain acyl-CoA synthetase 4 as a target or target, and the corresponding drug can be easily obtained or screened by one skilled in the art based on the results of the present study. These agents may be those which inhibit the activity of long chain acyl-coa synthetase 4, rendering it biologically non-functional; or inhibiting the expression of the long-chain acyl-CoA synthetase 4 gene, such as inhibiting transcription or translation, and the like, and the medicines treat the Parkinson disease by taking the long-chain acyl-CoA synthetase 4 as a target point, which belong to the protection scope of the invention.
In another aspect, the present invention provides a method for preparing a medicament for preventing or treating parkinson's disease, comprising: the inhibitor of the long-chain acyl coenzyme A synthetase 4 is taken as a main active component and is mixed with pharmaceutically acceptable auxiliary materials.
Based on the disclosure of the invention, the invention provides a novel method for preparing a drug for treating Parkinson's disease, which takes an inhibitor of long-chain acyl-CoA synthetase 4 as a main active ingredient. The prepared medicine can treat Parkinson's disease.
Alternatively, in some embodiments of the invention, the inhibitor is selected from any one of triacin C and pioglitazone.
Alternatively, in some embodiments of the invention, the inhibitor is a viral vector that inhibits the expression of long chain acyl-coa synthetase 4.
Optionally, in some embodiments of the invention, the viral vector is an adeno-associated viral vector.
Alternatively, in some embodiments of the invention, the adeno-associated viral vector is an AAV8 viral vector.
It should be noted that the pharmaceutically acceptable excipients are reasonably selected by those skilled in the art according to the needs, and any selected excipients belong to the protection scope of the present invention.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 shows the expression levels of long-chain acyl-CoA synthetase 4 significantly different between Parkinson's disease patients and age-matched normal persons;
in the figure:
a: analyzing the data of a human-derived substantia nigra transcriptomics database GSE20141, and finding that the expression of the substantia nigra long-chain fatty acyl coenzyme A synthetase 4 gene (ENSG00000068366) of the Parkinson patient is increased;
b: when the human serum ACSL4 transcriptomics (gene number: NM-004458.1) data are analyzed, the expression of the serum ACSL4 of the patient with the Parkinson's disease is increased compared with that of a younger normal control;
c: when the human serum ACSL4 transcriptomics (gene number: NM-022977.1) data are analyzed, the serum ACSL4 of the patient with the Parkinson disease expresses the increased normal control of the older people.
FIG. 2 shows that there is significant dyskinesia and abnormal expression of long-chain acyl-CoA synthetase 4 in Parkinson's disease model mice;
in the figure:
a: detecting the expression level of Tyrosine Hydroxylase (TH) in the substantia nigra region of the brain of a Parkinson disease model mouse and a control group mouse by Western Blot;
b: detecting the movement capability of the Parkinson disease model mouse and the control group mouse by climbing rod test, and comparing the Time to turn Time of the Parkinson disease model mouse and the control group mouse;
c: the open field test measures the motor capacity of the model mouse with Parkinson's disease and the control group mouse, and compares the motor Speed of the two (AmBulatory episodies Average Speed).
FIG. 3 is a panel showing that AAV 8-mediated ACSL4 Knock-out (KO) can alleviate dyskinesia in a Parkinson's disease model mouse;
in the figure:
a: testing and detecting the movement capacity of a Parkinson disease model mouse injected with the ACSL4 knockout virus and mice of a control group thereof by climbing a rod, and comparing the turn-around Time (Time to turn) of the three groups;
b: detecting the movement capacity of the Parkinson disease model mouse injected with the ACSL4 knockout virus and the mouse of a control group thereof by a rotating rod test, and comparing the residence time (Latency to fall) of the three groups of mice on a rod;
c/d: gait tests the motion ability of the mouse model of Parkinson's disease injected with ACSL4 knockout virus and the control group mouse thereof, and respectively counts the step width and the motion disorder coefficient of the three groups of mice; fore stands for forefoot, Hind stands for Hind, Left Fore stands for Left forefoot, Right Fore stands for Right forefoot, Left Hind stands for Left Hind, Right Hind stands for Right Hind;
e: the expression level of the ACSL4 in the substantia nigra region in the brain of mice injected with the ACSL4 knockout virus and control mice thereof is detected by western blot.
FIG. 4 is a graph of AAV 8-mediated death of dopamine neurons in mice in the model Parkinson's disease reversed by ACSL4 KO;
in the figure:
a/b: detecting the expression level of Tyrosine Hydroxylase (TH) in substantia nigra region in brains of a Parkinson disease model mouse injected with the ACSL4 knockout virus and a control group mouse of the mouse by using western blot, and counting;
c/d: the number of tyrosine hydroxylase positive neurons in substantia nigra areas in brains of mice of Parkinson disease model injected with ACSL4 knockout virus and mice of a control group thereof are detected by immunohistochemical staining and counted by a stereomicroscope.
FIG. 5 shows that treatment with the inhibitor Triacsin C of ACSL4 can significantly alleviate dyskinesia of mice model with Parkinson's disease;
in the figure:
a: detecting the movement capacity of a Parkinson disease model mouse and a control group mouse of the Triacsin C administrated through a nasal cavity by a climbing rod test, and comparing the turn-around Time (Time to turn) of three groups of mice;
b: open field testing was performed to examine the motility of the parkinsonism model mice nasally dosed with Triacsin C and their control mice, and the motility speeds of the three groups of mice were compared (album episodies Average Speed);
c: western blot was used to detect the expression level of Tyrosine Hydroxylase (TH) in substantia nigra region in brain of Parkinson disease model mice treated with nasal Triacsin C administration and control mice, and statistics was performed.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Statistical analysis of transcriptome data in which long-chain acyl-coa synthetase 4 was performed based on published data of the human source database GSE20141 revealed that long-chain acyl-coa synthetase 4 gene (ENSG00000068366) expression was increased in SNpc (a in fig. 1) and gene expression was also increased in serum (b, c in fig. 1) in parkinson's disease patients.
Example 2
1-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine (MPTP) can be dehydrogenated in substantia nigra cells to generate MPP+Ions, which inhibit mitochondrial complex enzymes, cause the cell to die. MPTP is one of the commonly used drugs for making animal models of Parkinson's disease.
C57 mice were injected intraperitoneally with MPTP (20mg/kg), four times for eight hours, once every two hours. Behavioral tests were performed from day 19 to day 21 post injection. The climbing pole test shows that the time of turning the head of the mice injected with the MPTP is obviously longer, the open field test shows that the movement speed of the mice injected with the MPTP is obviously slowed down, and the movement capability of the mice is damaged (b and c in figure 2); mice were euthanized on day 21, and after PBS perfusion, the left cerebral substantia nigra was taken to detect the expression of Tyrosine hydroxylase (Tyrosine hydroxylase) and ACSL4, and the right brain was immersed in 4% paraformaldehyde, and the number of dopamine nerves was detected by pathological section. The results show that: the expression of tyrosine hydroxylase at the substantia nigra part of the mouse model of the Parkinson disease is obviously reduced, the expression of ACSL4 is obviously increased (a in figure 2), and the behavioral detection reflects that the motor ability of the mouse model of the Parkinson disease is seriously damaged (b and c in figure 2).
Example 3
The AAV viral vector has the advantages of safety, high efficiency, low toxicity and the like when applied in vivo in the nervous system, and is very suitable for the research of the nervous system. The AAV8-ACSL4 viral vector capable of knocking out mouse ACSL4 gene is injected at the substantia nigra part of a mouse, so that the expression of the substantia nigra ACSL4 is knocked down (e in figure 3), a Parkinson disease MPTP model is constructed 30 days after virus injection, and the protective effect of the substantia nigra ACSL4 knock-out on the Parkinson disease model is evaluated through behavior detection and pathological section detection. The results show that: AAV 8-mediated knockout of the ACSL4 gene was able to alleviate dyskinesia (a-d in fig. 3) and rescue the decrease in tyrosine hydroxylase expression after MPTP modelling (a, b in fig. 4) and reduce dopamine neuron death (c, d in fig. 4) in parkinson's disease model mice.
Example 4
The Triacsin C is derived from Streptomyces aureus (Streptomyces aureus), is a natural intracellular long-chain acyl-coenzyme A synthetase (ACSL) inhibitor, and can effectively inhibit the activity of ACSL1 and ACSL 4. By intraperitoneal injection of an MPTP model (the dose is the same as that in example 1), 25ul of 5mg/mL of triacin C is injected into the nasal cavity from the next day of molding, 8 days of continuous injection are carried out, the triacin C treatment effect is detected by behavior from 19 days to 21 days after MPTP molding, a mouse is killed at 21 days, perfusion is carried out, the left substantia nigra of the brain tissue of the mouse is collected, and the right brain tissue is soaked in 4% paraformaldehyde for subsequent pathological section. As a result: after 8 days of triacin C treatment, the dyskinesia of the PD model mouse can be obviously relieved (a and b in figure 5), and the expression level of the dopamine neuron marker tyrosine hydroxylase in the substantia nigra of the PD model mouse can be improved (C in figure 5).
The above results fully demonstrate that ACSL4 can be used as a target for treating parkinson's disease, and that by administering an inhibitor of ACSL4 to a patient with parkinson's disease, for example, it can improve symptoms associated with parkinson's disease, such as relief of dyskinesia, reduction of expression decrease of tyrosine hydroxylase, reduction of dopamine neuron death, and the like.
The correlation detection method in the above embodiment is as follows:
(1) western blotting (Western Blot)
1) Protein collection and concentration determination: homogenizing the dissected tissue in a 4 ℃ lysis solution, and standing for 15-20 minutes after homogenizing; or the collected cells were left to stand in a lysis solution at 4 ℃ for 30 minutes. 13000g was centrifuged at 4 ℃ for 20 minutes and the supernatant was collected. Take 96-well plates and repeat 3 wells for each sample. Add 18. mu.L PBS, 2. mu.L of the extracted supernatant, and 200. mu.L BCA solution to each well, mix well, and incubate for 30 min at 37 ℃. Absorbance was measured at 562 nm. The protein concentration (. mu.g/. mu.L) was calculated from a standard curve relating protein concentration to absorbance.
2) Preparing a sample loading system: according to the possible content ratio of the target protein in the total extracted protein and the concentration of the extracted total protein, 20-50 mu g of the total protein is taken for electrophoretic separation. For example, a 20. mu.L system containing 20. mu.g of protein was prepared, and the calculated volume of protein solution, 2. mu.L of 10X Reducing agent, 5. mu.L of 4X Sample loading buffer were added to the system, and 20. mu.L of distilled water was added to make up. The system was denatured for 5 minutes at 100 ℃.
3) Loading and electrophoresis: and (4) directly loading the sample system into the prefabricated gel loading hole after the sample system is cooled to room temperature. Leaving one hole to add a protein molecular weight reference marker' See
Pluse2 Prestained Marker ". The electrophoresis time is about 1 hour generally, and the electrophoresis can be stopped when the electrophoresis indicator approaches the bottom end of the electrophoresis gel, and then the membrane is transferred.
4) Film transfer: the PVDF membrane and filter paper of appropriate size are sheared. Activating the cut PVDF membrane in methanol for 2-10s, and changing color for use. The filter paper, sponge pad, activated membrane were then placed in a tray with transfer fluid. The gel was peeled off the clamp and placed in a tray containing the transfer solution. The glue, the membrane, the filter paper and the sponge in the transfer liquid tray are arranged in the order of sponge, three layers of filter paper, glue, membrane, three layers of filter paper and sponge from the negative electrode to the positive electrode. The whole process is carried out in a tray with a transfer buffer. After the membrane structure is converted, the membrane is placed into a membrane conversion clamp, then placed into a membrane conversion groove, filled with membrane conversion buffer solution, and then placed into a chromatography cabinet at 4 ℃, and generally transferred for 1h by 100V, which is determined according to the size of protein.
5) Immune reaction: the PVDF membrane containing the protein band was removed and the PBS was slightly rinsed, transferred with tweezers to a dish containing 5% skim milk powder blocking solution, and blocked by shaking on a horizontal shaker at room temperature for 1 h. After blocking, the blocking solution was removed and washed with appropriate amount of TBST (just by flooding the membrane) on a horizontal shaker at room temperature for 2 times, 5 minutes each time. Primary antibodies were diluted to the appropriate concentration with TBST (see antibody instructions, determine dilution factor), plated off, antibody added, and placed on a horizontal shaker at 4 ℃ overnight. The primary antibody was recovered or decanted and washed 3 times with TBST on a horizontal shaker at room temperature for 5 minutes each. The secondary antibody was diluted to the appropriate concentration with TBST and incubated for 1h at room temperature. The secondary antibody was removed and washed 3 times with TBST on a room temperature water pan for 10 minutes each, followed by a chemiluminescent reaction.
6) And (3) chemiluminescence development: the developing solution is prepared and used at present according to the preparation proportion of the specification. And (3) placing the film in a developing instrument, dropwise adding a luminous liquid, setting exposure parameters, and finely adjusting the exposure time according to an exposure result. The exposure results will be used for subsequent statistical analysis.
(2) Immunohistochemistry by an enzyme:
1) and (3) film washing: sections were washed 3 times with PBS for 5 minutes each.
2) And (3) sealing: standing and sealing for 1 hour at room temperature, sealing liquid: 0.3% Triton X-100+ 5% NGS in 1 xPBS.
3) A first antibody: antibodies were diluted with blocking solution and incubated overnight at 4 ℃ according to antibody specification recommended concentrations. The antibody solution was then removed and the sections were washed 3 times with 0.2% Tween-20in 1xPBS for 5 minutes each.
4) Secondary antibody: secondary antibodies with HRP (horseradish peroxidase) labels were diluted with blocking solution at the recommended concentration according to the antibody instructions and incubated for 2 hours at room temperature. The antibody solution was then removed and the sections were washed 3 times with 0.2% Tween-20in 1xPBS for 5 minutes each.
5) Color development: further labeling was performed using DAB. DAB is configured according to the reagent specification, and under the observation of a microscope, when brown-yellow positive particles appear in the target tissue and no nonspecific color is developed in the surrounding tissue, distilled water is stopped, and DAB solution is washed away.
6) Sealing: a neutral gum mounting was used.
(3) Pole climbing test:
mice were placed vertically on vertical wooden poles 1cm in diameter and 50 cm high. Adaptation is carried out one day (day 1) before testing, and the concrete operation is that the mouse head is placed at the top end of a wood pole upwards, and the mouse slides downwards or turns around to climb to the ground according to the mouse head, and five times of tests are continuously carried out. Then, on the test day (day 2), the whole pole climbing process of the mouse is recorded through video recording software, and after the experiment is finished, the time interval (turning time, T) from the head part to the turning body part of the mouse is analyzed according to the recorded videoturn) And the time interval (completion time, T) from the top of the wooden pole completely down to the groundcomplete). Five trials were performed per mouse and the average was used for analysis.
(4) Bar rotation test (3 b):
the mice were placed on a rotarod apparatus running at a constant speed of 4r/min, and the acceleration program was started (acceleration from 4r/min to 40r/min in 5 minutes). The time from the start to the time of the mice drop was recorded. Each mouse was repeated 3 times with 30 min intervals, and the mean was taken for statistical analysis.
(5) Open field test (2c,5 b):
the mice free activity was recorded infra-red using the ENV-510 behavior monitoring system of Med Association. Specifically, the mouse is placed in a transparent box with the length multiplied by 27.31cm multiplied by 20.32cm (length multiplied by width multiplied by height), the door of the box is closed, the box is adapted for 10 minutes, and parameters such as the moving distance, the moving time, the average speed and the like of the mouse within 50 minutes are recorded.
(6) Gait test (3c,3 d):
the walking gait of the mice was quantitatively analyzed using the DigiGaitTM imaging system. Specifically, a mouse is placed on a transparent mechanical running belt to walk, the running speed of the running belt is 15cm/s (the speed is determined according to a pre-experiment according to the fact that the mouse can stably crawl at the speed and is not searchable or foraging sample walking at a low speed or incapable of walking at a high speed), a high-speed camera records a video of about 1 minute of crawling of the mouse, and the video which runs stably for about 4s is selected to be analyzed. Digigait 8 software can identify the area and time of the front limb and the rear limb of a mouse contacting with the running belt in a video recorded by a high-speed camera, and further counts posture and kinematics indexes of multiple gait dynamics.
(7) The AAV8-ACSL4 virus vector preparation method comprises the following steps:
the mouse ACSL4 cDNA was introduced into the AgeI and SacI cleavage plasmid pssAAV-cp-egfp to generate pssAAV-mACSL 4. The sgRNA for knocking out ACSL4 is designed, the sgRNA is connected with a pssAAV-mACSL4 vector, and the editing efficiency of the connected vector is screened. The serum 8 type rAAV vector (rAAV8) is prepared by knocking out ACSL4 pssAAV-mACSL4-sp.g3 and eGFP expression plasmid pssAAV-CB-eGFP. All rAAV8 vectors were generated in human embryonic kidney 293 cells using a three-plasmid co-transfection method. rAAV8 vector was collected 72 hours post transfection and subjected to two rounds of CsCl gradient ultracentrifugation purification followed by silver staining and genomic copy titration.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of an inhibitor of long chain acyl-coa synthetase 4 in the manufacture of a medicament for the prevention or treatment of parkinson's disease.
2. The use according to claim 1, wherein the inhibitor is selected from any one of Triacsin C and pioglitazone.
3. The use of claim 1, wherein the inhibitor is a viral vector that inhibits the expression of long chain acyl-coa synthetase 4.
4. The use of claim 3, wherein the viral vector is an adeno-associated viral vector;
preferably, the adeno-associated viral vector is an AAV8 viral vector.
5. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an injection.
6. A medicament for preventing or treating Parkinson's disease, which is characterized in that the medicament takes long-chain acyl-CoA synthetase 4 or a coding gene thereof as a target point, and inhibits the activity or the expression level of the long-chain acyl-CoA synthetase 4.
7. A method for preparing a medicament for preventing or treating parkinson's disease, comprising: the inhibitor of the long-chain acyl coenzyme A synthetase 4 is taken as a main active component and is mixed with pharmaceutically acceptable auxiliary materials.
8. The method according to claim 7, wherein the inhibitor is selected from any one of Triacsin C and pioglitazone.
9. The method of claim 7, wherein the inhibitor is a viral vector that inhibits the expression of long-chain acyl-CoA synthetase 4.
10. The method of claim 9, wherein the viral vector is an adeno-associated viral vector;
preferably, the adeno-associated viral vector is an AAV8 viral vector.
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