New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome
Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and deve...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.1110163/full |
| _version_ | 1828065740371001344 |
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| author | Pierre Conan Alice Léon Noéline Caroff Claire Rollet Loubna Chaïr Jennifer Martin Frédéric Bihel Olivier Mignen Cécile Voisset Gaëlle Friocourt |
| author_facet | Pierre Conan Alice Léon Noéline Caroff Claire Rollet Loubna Chaïr Jennifer Martin Frédéric Bihel Olivier Mignen Cécile Voisset Gaëlle Friocourt |
| author_sort | Pierre Conan |
| collection | DOAJ |
| description | Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS. |
| first_indexed | 2024-04-10T23:18:49Z |
| format | Article |
| id | doaj.art-806da89a4161444b8b1e28fac97c6929 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-10T23:18:49Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-806da89a4161444b8b1e28fac97c69292023-01-12T16:58:30ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-01-011610.3389/fnins.2022.11101631110163New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndromePierre Conan0Alice Léon1Noéline Caroff2Claire Rollet3Loubna Chaïr4Jennifer Martin5Frédéric Bihel6Olivier Mignen7Cécile Voisset8Gaëlle Friocourt9INSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceLaboratoire d’Innovation Thérapeutique, UMR 7200, IMS MEDALIS, Faculty of Pharmacy, CNRS, Université de Strasbourg, Illkirch, FranceU1227, Lymphocytes B, Autoimmunité et Immunothérapies, INSERM, Université de Brest, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceINSERM, Université de Brest, EFS, UMR 1078, GGB, Brest, FranceDown syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.https://www.frontiersin.org/articles/10.3389/fnins.2022.1110163/fullCBSDYRK1AGSK3βAktNF-κBpharmacological inhibitor |
| spellingShingle | Pierre Conan Alice Léon Noéline Caroff Claire Rollet Loubna Chaïr Jennifer Martin Frédéric Bihel Olivier Mignen Cécile Voisset Gaëlle Friocourt New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome Frontiers in Neuroscience CBS DYRK1A GSK3β Akt NF-κB pharmacological inhibitor |
| title | New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome |
| title_full | New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome |
| title_fullStr | New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome |
| title_full_unstemmed | New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome |
| title_short | New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome |
| title_sort | new insights into the regulation of cystathionine beta synthase cbs an enzyme involved in intellectual deficiency in down syndrome |
| topic | CBS DYRK1A GSK3β Akt NF-κB pharmacological inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.1110163/full |
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