CN113499335A - Medicine for treating neurodegenerative diseases by targeted autophagy fusion - Google Patents
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The invention discloses application of 13-cis retinoic acid in preparation of a medicament for treating neurodegenerative diseases. The inventor finds that the carrot-like substance 13-cis retinoic acid can target STX17 and SNAP29 and promote the interaction of mediating autophagy fused SNARE protein, so that the level of mitochondrion autophagy of primary nerve cells of a kansl 1-deficient mouse is effectively improved, and the abnormality of dendritic spines of kansl1 heterozygous mouse neurons and the defect of learning and memory ability can be effectively improved. This finding suggests that the 13-cis retinoic acid material has potential application value in the treatment of neurodegenerative diseases associated with coulomb-de-fries syndrome, with abnormal mitochondrial autophagy, and with abnormal expression of STX17 or SNAP29 genes.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of 13-cis retinoic acid in preparation of a medicine for treating neurodegenerative diseases.
Background
Autophagy is a programmed intracellular degradation process [ Physiological reviews 90,1383-1435(2010) ]. When autophagy occurs, autophagosomes wrap proteins or organelles to be degraded, such as mitochondria, and are fused with lysosomes under the action of two SNARE protein complexes (STX17-SNAP29-VAMP8 and YKT6-SNAP29-STX7) to complete degradation [ Cell 151,1256-1269 (2012); the Journal of cell biology 217,2633-2645 (2018). This process is a key pathway for cells to maintain homeostasis, and is especially critical for terminally differentiated and mitochondria-functionally active cells, such as neurons. Deletion of many important autophagy genes is known to cause neuronal dysfunction; the occurrence of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease, is closely related to the disorder of autophagy [ Nature reviews. molecular cell biology 19,349-364(2018) ].
Coulomb-de-fries syndrome is a rare disease due to insufficient haplotypes of KANSL1 [ Nature genetics 44, 639-; european journal of human genetics: EJHG 24, 652-. The disease is a systemic disorder, manifested by varying degrees of mental retardation, cardiac dysfunction, muscle tone relaxation and specific facial features, among which mental retardation is the most prominent feature of the disease [ Cytogenetic and genome research 114,89-92 (2006); BMC clinical genetics 16,68 (2015). The pathological mechanism of the disease is unknown so far, and no effective treatment means exists.
13-cis retinoic acid, also known as isotretinoin, is an FDA drug for the treatment of acne [ JAMAdermatology (2019) ]. 13-cis retinoic acid is converted into all-trans retinoic acid by isomerase in vivo, and is a metabolic active substance of β -carotene [ Nature reviews. neuroscience 8,755-765(2007) ]. Beta-carotene is converted into retinaldehyde by oxidative shear in vivo, and the retinaldehyde is converted into retinoic acid by oxidation.
Disclosure of Invention
The invention aims to disclose the correlation between the coulomb-Fries syndrome and autophagy fusion abnormality and provide a new medicinal application of 13-cis retinoic acid.
The correlation between the coulomb-de-fries syndrome and autophagy fusion abnormality disclosed by the invention is as follows: the deletion of the disease-causing gene KANSL1 of the coulomb-de-Fries syndrome leads to the down-regulation of the expression of the autophagy fusion key protein STX17, and further leads to the dysfunction of autophagy and mitochondrion autophagy.
The new application of the 13-cis retinoic acid medicine provided by the invention is as follows: use of 13-cis retinoic acid in the preparation of:
1) drugs for treating neurodegenerative diseases;
2) a medicament for the treatment of coulomb-de-fries syndrome;
3) a medicament for treating a neurodegenerative disease associated with coulomb-de-fries syndrome;
4) a medicament for treating a neurodegenerative disease associated with abnormal mitochondrial autophagy;
5) a medicament for treating neurodegenerative diseases related to autophagy fusion abnormality caused by abnormal expression of STX17 or SNAP29 gene.
In the application, the coulomb-de-fries syndrome is the coulomb-de-fries syndrome caused by the insufficiency of the single-gene single dose of KANSL 1.
The 13-cis retinoic acid comprises 13-cis retinoic acid raw drug (CAS number: 4759-48-2), Biotin-13-cis retinoic acid, isotretinoin (CAS number: 78147-42-9) and pharmaceutically acceptable salts, esters and hydrates thereof.
The invention also provides a medicament for treating neurodegenerative diseases, which comprises a 13-cis retinoic acid raw drug, Biotin-13-cis retinoic acid, isotretinoin and pharmaceutically acceptable salts, esters and hydrates thereof.
The invention also provides a medicament for treating the coulomb-de-fries syndrome, which comprises a 13-cis retinoic acid raw drug, Biotin-13-cis retinoic acid, isotretinoin, and pharmaceutically acceptable salts, esters and hydrates thereof.
The present invention also provides a medicament for treating neurodegenerative diseases associated with coulomb-de-fries syndrome, abnormal mitochondrial autophagy, and abnormal expression of STX17 or SNAP29 genes leading to abnormal autophagy fusion [ Proceedings of the National Academy of Sciences of the United States of America 116,556-565 (2019); autophagy 4, 590-; the Journal of biological chemistry 287,32861-32873 (2012); nature media 24,313-325 (2018); the Journal of cell biology 200,731-741 (2013); autophagy 11,1608-1622(2015), said drug comprises 13-cis retinoic acid technical drug, Biotin-13-cis retinoic acid, isotretinoin, and pharmaceutically acceptable salts, esters, and hydrates thereof.
The above drugs can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The invention also provides a method of treating neurodegenerative diseases, related to coulomb-de-fries syndrome or coulomb-de-fries syndrome, related to abnormal mitochondrial autophagy, and related to abnormal expression of STX17 or SNAP29 genes.
The method for treating neurodegenerative diseases, related to the coulomb-de-fries syndrome or the coulomb-de-fries syndrome, related to mitochondrial autophagy abnormality and related to autophagy fusion abnormality caused by abnormal expression of STX17 or SNAP29 genes, provided by the invention, comprises the following steps of: the 13-cis retinoic acid technical material, Biotin-13-cis retinoic acid, isotretinoin and other salts, esters and hydrates of the technical material are given to patients in corresponding doses (0.5-2 mg/kg/day).
The inventors of the present invention found that the KANSL1 gene deletion resulted in significant down-regulation of the expression of the autophagy fusion key gene STX 17; by constructing a whole body knockout mouse of kansl1 and a heterozygous mouse, and using a mitoKeima transgenic mouse of a mitophagy probe, the primary nerve cell mitophagy level of a kansl 1-deficient mouse is found to be abnormal. Through a classical 'new thing recognition experiment' and a 'water maze experiment', the heterozygous mouse is found to show the decline of learning and memory ability; through pathological analysis, the number of the hippocampal dendritic spines of the heterozygous mice is reduced, and the arrangement is disordered. The inventor finds that the carrot-like substance 13-cis retinoic acid can target STX17 and SNAP29 and promote the interaction of mediating autophagy fused SNARE protein, so that the level of mitochondrion autophagy of primary nerve cells of a kansl 1-deficient mouse is effectively improved, and the abnormality of dendritic spines of kansl1 heterozygous mouse neurons and the defect of learning and memory ability can be effectively improved. This finding suggests that the 13-cis retinoic acid material has potential application value in the treatment of neurodegenerative diseases associated with coulomb-de-fries syndrome, with abnormal mitochondrial autophagy, and with abnormal expression of STX17 or SNAP29 genes.
Drawings
Figure 1 is a KANSL1 deletion down-regulating expression of STX 17.
FIG. 2 shows the chemical structure of 13-cis retinoic acid.
FIG. 3 is a graph showing that 13-cis retinoic acid is capable of binding to STX17 and SNAP 29.
FIG. 4 is a 13-cis retinoic acid facilitated interaction mediating autophagy fusion SNARE proteins.
FIG. 5 is a graph of abnormalities in the level of mitochondrial autophagy of primary neurons in kansl1 deficient mice that were improved by 13-cis retinoic acid.
FIG. 6 is a graph showing that 13-cis retinoic acid is able to alleviate abnormalities in neuronal dendritic spines in kansl1 heterozygous mice.
FIG. 7 is a graph showing that 13-cis retinoic acid improves cognition in kansl1 heterozygous mice.
FIG. 8 shows that 13-cis retinoic acid can improve spatial learning and memory of kansl1 heterozygous mice.
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
The invention provides an application of 13-cis retinoic acid in preparation of the following products:
1) drugs for treating neurodegenerative diseases;
2) a medicament for the treatment of coulomb-de-fries syndrome;
3) a medicament for treating a neurodegenerative disease associated with coulomb-de-fries syndrome;
4) a medicament for treating a neurodegenerative disease associated with abnormal mitochondrial autophagy;
5) a medicament for treating neurodegenerative diseases related to autophagy fusion abnormality caused by abnormal expression of STX17 or SNAP29 gene.
In the application, the coulomb-de-fries syndrome is the coulomb-de-fries syndrome caused by the insufficiency of the single-gene single dose of KANSL 1.
The 13-cis retinoic acid comprises a 13-cis retinoic acid raw drug, Biotin-13-cis retinoic acid, isotretinoin, and other salts, esters and hydrates of the drug.
The inventors of the present invention found that the KANSL1 gene deletion resulted in significant down-regulation of the expression of the autophagy fusion key gene STX 17; by constructing a whole body knockout mouse of kansl1 and a heterozygous mouse, and using a mitoKeima transgenic mouse of a mitophagy probe, the primary nerve cell mitophagy level of a kansl 1-deficient mouse is found to be abnormal. Through a classical 'new thing recognition experiment' and a 'water maze experiment', the heterozygous mouse is found to show the decline of learning and memory ability; through pathological analysis, the number of the hippocampal dendritic spines of the heterozygous mice is reduced, and the arrangement is disordered. The inventor finds that the carrot-like substance 13-cis retinoic acid can target STX17 and SNAP29 and promote the interaction of mediating autophagy fused SNARE protein, so that the level of mitochondrion autophagy of primary nerve cells of a kansl 1-deficient mouse is effectively improved, and the abnormality of dendritic spines of kansl1 heterozygous mouse neurons and the defect of learning and memory ability can be effectively improved. This finding suggests that the 13-cis retinoic acid material has potential application value in the treatment of neurodegenerative diseases associated with coulomb-de-fries syndrome, with abnormal mitochondrial autophagy, and with abnormal expression of STX17 or SNAP29 genes.
Example 1, loss of KANSL1 down-regulated STX17 expression.
1) KANSL1 knockdown. KANSL1 siRNA was transfected in HeLa cells using Lipofectamine RNAiMAX (Thermo Fisher) transfection reagent. After 60h of transfection, HeLa cells were lysed with RIPA lysate, and the change in expression level of STX17 protein was detected by Western blot.
2) And (5) experimental results. KANSL1 knockdown significantly down-regulated the protein level of STX17 (as shown in figure 1).
Example 2, 13-cis retinoic acid binds to STX17 and SNAP29 and promotes interaction between SNARE proteins.
1) Biotin-13-cis retinoic acid pulldown experiment. Biotin is coupled with 13-cis retinoic acid to synthesize a Biotin-13-cis retinoic acid compound. Biotin and Biotin-13-cis retinoic acid at a final concentration of 5. mu.M were added to HeLa cells for 24 hours, and the cells were starved for 2 hours by EBSS and harvested. Streptavidin Agarose beads (Thermo,20357) were incubated overnight with the cell lysates and Western blot was used to detect the expression of each protein.
2) 13-cis retinoic acid promotes interactions that mediate autophagic fusion SNARE proteins. Stably knocking down KANSL1 in HeLa cells by using shRNA-expressing lentivirus and using TurboFectTMTransfection Reagent (Invitrogen, R0531), and Flag-Snap29 was transiently overexpressed in the cells. After 24 hours of transfection, 13-cis retinoic acid at a final concentration of 5 μ M was added to HeLa cells for 24 hours, and the cells were starved for 2 hours by EBSS and harvested. anti-Flag M2 affinity gel (Sigma-Aldrich, A2220) was incubated overnight with the cell lysates and Western blot was used to detect the expression of each protein.
3) And (5) experimental results. The results of the Biotin-13-cis retinoic acid pulldown experiments show that Biotin-13-cis retinoic acid can bind to STX17 and SNAP29 (shown in FIG. 3); co-immunoprecipitation experimental results showed that 13-cis retinoic acid enhanced the interaction of STX17, VAMP8, STX7 and YKT6 with SNAP29 protein and reversed the reduction of interaction of STX17 and VAMP8 with SNAP29 caused by KANSL1 deletion (as shown in fig. 4).
Example 3, 13-cis retinoic acid improved abnormalities in the level of mitophagy in primary neurons of kansl1 deficient mice.
1) Construction of kansl1-/-Induced condition knockout mice. kansl1loxp/loxpConstruction of mice: the third exon of kansl1 gene was edited by Turbocknockout technology using C57BL/6 embryonic stem cells as target cells, and finally the whole gene was mutated with loss of function, which was completed by Sci Biotech, Inc. By combining this mouse with a CAG-cre mouse [ origin C57BL/6(004682, Jackson Laboratory)]And mitoKeima (mitochondrial autophagy probe protein) transgenic mice [ from C57BL/6(028072, Jackson Laboratory)]After hybridization, kansl1 was obtained-/-An inducible conditional knockout mouse;
2) and (3) separating and culturing primary neurons. Taking E14.5 day gestational age fetal rat, taking out cortex tissue, cutting, digesting into single cells, and planting in different pore plates and cavities according to proper density. And performing in-vitro differentiation culture. On day 5 of differentiation, 1 μ M tamoxifen was added and the drug was withdrawn. Changing the liquid to be neuron culture medium without vitamin A to culture the neurons, adding 20 mu M13-cis retinoic acid on the 6 th day of differentiation, culturing for 24h, and carrying out laser confocal shooting and quantitative analysis on mitoKeima fluorescence;
3) and (5) experimental results. The level of mitophagy of kansl 1-deficient mouse primary neurons was significantly reduced. After the neurons were dosed with 13-cis retinoic acid, the level of mitophagy of kansl 1-deficient mice primary neurons was enhanced. N-48, 52,43, 49 (each dot represents a cell). Results are mean ± SEM; the statistical method is One-wayAnnova (as shown in FIG. 5).
Example 4, 13-cis retinoic acid improved the abnormalities of dendritic spines in kansl1 heterozygous mice.
1) Construction of kansl1+/-A mouse. By mixing kansl1loxp/loxpThe washing background of the mice and EIIA-cre mice [ the source is B6.FVB-Tg (EIIa-cre) C5379Lmgd/J (003727, Jackson Laboratory) and C57BL/6 background mice are completed by mating for more than eight generations]Obtaining kansl1 heterozygous mice after hybridization;
2) 13-cis retinoic acid drug therapy. For 4 months old Kansl1+/-And Kansl1+/+Mice were injected intraperitoneally with 13 cis retinoic acid (0.5mg/kg/day) for one month;
3) golgi staining. Mice were perfused with 4% paraformaldehyde, brains were removed quickly, and the brains were soaked in a liquid A and liquid B mixture prepared one day in advance (the Kit was FD rapid GolgiStain Kit, a product of PK401 from FD Neuro Technologies, Inc.). The mixture was stored in the dark for 14 days, and the fresh solution A and solution B were replaced on day 2. The brain tissue was transferred to liquid C, and on day 2, fresh liquid C was replaced and soaked for 3 days. The tissue was frozen in isopentane on dry ice and sections of 100um thickness were cut in a cryomicrotome. The sections were stained in the mixture of solution D and solution E. And (5) conventionally dehydrating, and sealing the sheet by using a neutral resin adhesive. After the slides were air-dried, the CA1 area was scanned using a PE confocal laser microscope.
4) And (5) experimental results. The density of dendritic spines in a CA1 area of the hippocampus of the heterozygous mice is remarkably reduced. After the mice are dosed with 13-cis retinoic acid, the density of the dendritic spines of the heterozygous mice is increased. N-25, 26, 33, 31 (each group from 2 to 3 mice). Results are mean ± SEM; the statistical method is One-wayAnnova (as shown in FIG. 6).
Example 4, 13-cis retinoic acid enhances learning and memory in Kansl1 heterozygous mice
1) And (5) identifying and testing new things. Three days ahead, the mouse is placed in a room to adapt, the tension is reduced, the mouse is placed in a box to adapt for 10min in the period, and the tail number is marked; on the test day, 1# puts the object AA into the box, sets the background, puts the mouse head back to the object into the center of the box, records for 10 min; after 24h, the object AB is placed in the box in the No. 2 mode, the background is reset, the mouse is placed in the center of the box, 10min is recorded, the object is found when the distance between the nose tip and the object is less than 1cm, and the task of standing the object is invalid. The time for the mice to explore A and B in # 2 was counted, and the result of statistical analysis was found to be resolution ═ tB/(tB + tA). Each dot represents one mouse. Results are mean ± SEM; the statistical method is One-wayAnnova (as shown in FIG. 7).
As can be seen from fig. 7: the kansl1 heterozygous mice had significantly reduced recognition of the new event compared to wild mice; and the 13-cis retinoic acid can remarkably improve the new thing recognition capability of kansl1 heterozygous mice.
2) Water maze experiment. The mice were acclimated one week in advance, and the operators were played with the mice daily for touch. The diameter of the water maze pool is 122cm, and the diameter of the platform is 6 cm. The platform was placed in the southeast quadrant. 3 spatial reference objects are fixed on three fence columns of the water maze, and the patterns are respectively circular, triangular or square. The water pool stores water in advance, the water level is 1cm higher than the platform, the titanium dioxide is added before training, the mixture is fully stirred, the water in the water pool is not permeable, and the water temperature is 20-22 ℃. The mice were slowly placed in the water facing the pool wall parallel to the water surface. Recording the latency time of the mouse, if the latency time reaches 60s, informing an operator to guide the mouse to go up to the platform, staying on the platform for 20s and taking away after being familiar with the surrounding environment; if the mouse is upstream of the platform within 60s latency and stays on the platform for 5s, the mouse is allowed to continue on the platform for 15s and then is taken away after familiarity with the surrounding environment. After the mice were taken out of the pool, the fur was wiped off with a dry towel and returned to the cage. After each round of testing is completed, all mice are trained for 4 times a day at intervals of more than 30 min. Training was performed for a total of 4 days. N-4 tests (from 5 to 7 mice per group). Results are mean ± SEM; the statistical method was Two-wayAnnova (as shown in FIG. 8).
As can be seen from fig. 8: the spatial learning and memory ability of the kansl1 heterozygous mouse is obviously reduced compared with that of a wild mouse; and the 13-cis retinoic acid can remarkably improve the spatial learning and memory capacity of kansl1 heterozygous mice.
Claims (7)
- The application of 13-cis retinoic acid in preparing the following products:1) drugs for treating neurodegenerative diseases;2) a medicament for the treatment of coulomb-de-fries syndrome;3) a medicament for treating a neurodegenerative disease associated with coulomb-de-fries syndrome;4) a medicament for treating a neurodegenerative disease associated with abnormal mitochondrial autophagy;5) a medicament for treating neurodegenerative diseases related to autophagy fusion abnormality caused by abnormal expression of STX17 or SNAP29 gene.
- 2. Use according to claim 1, characterized in that: in the application, the coulomb-de-fries syndrome is the coulomb-de-fries syndrome caused by the insufficiency of the single-gene single dose of KANSL 1.
- 3. Use according to claim 1 or 2, characterized in that: the 13-cis retinoic acid comprises a 13-cis retinoic acid raw drug, Biotin-13-cis retinoic acid, isotretinoin and pharmaceutically acceptable salts, esters and hydrates thereof.
- 4. A medicine for treating neurodegenerative diseases contains 13-cis retinoic acid, Biotin-13-cis retinoic acid, isotretinoin, and pharmaceutically acceptable salts, esters, and hydrates thereof.
- 5. A medicine for treating coulomb-de-fries syndrome contains 13-cis retinoic acid, Biotin-13-cis retinoic acid, isotretinoin, and pharmaceutically acceptable salts, esters, and hydrates thereof.
- 6. A medicine for treating the neurodegenerative diseases associated with Coulomb-De-Fries syndrome contains 13-cis retinoic acid, Biotin-13-cis retinoic acid, isotretinoin, and its pharmaceutically acceptable salts, esters and hydrates.
- 7. A medicine for treating the neurodegenerative diseases associated with the abnormal mitophagy and the abnormal autophagy fusion caused by the abnormal expression of STX17 or SNAP29 gene contains 13-cis-retinoic acid, Biotin-13-cis-retinoic acid, isotretinoin, and its pharmacologically acceptable salts, esters and hydrates.
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