The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes
Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affec...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-11-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.1007531/full |
| _version_ | 1811312701986570240 |
|---|---|
| author | Patricia Cogram Patricia Cogram Luis C. Fernández-Beltrán María José Casarejos Sonia Sánchez-Yepes Eulalia Rodríguez-Martín Alfonso García-Rubia Alfonso García-Rubia María José Sánchez-Barrena Carmen Gil Ana Martínez Ana Martínez Alicia Mansilla Alicia Mansilla |
| author_facet | Patricia Cogram Patricia Cogram Luis C. Fernández-Beltrán María José Casarejos Sonia Sánchez-Yepes Eulalia Rodríguez-Martín Alfonso García-Rubia Alfonso García-Rubia María José Sánchez-Barrena Carmen Gil Ana Martínez Ana Martínez Alicia Mansilla Alicia Mansilla |
| author_sort | Patricia Cogram |
| collection | DOAJ |
| description | Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability in situ and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker. |
| first_indexed | 2024-04-13T10:41:21Z |
| format | Article |
| id | doaj.art-5be53579afca493db46daa91c8c05468 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-13T10:41:21Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-5be53579afca493db46daa91c8c054682022-12-22T02:49:55ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-11-011610.3389/fnins.2022.10075311007531The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypesPatricia Cogram0Patricia Cogram1Luis C. Fernández-Beltrán2María José Casarejos3Sonia Sánchez-Yepes4Eulalia Rodríguez-Martín5Alfonso García-Rubia6Alfonso García-Rubia7María José Sánchez-Barrena8Carmen Gil9Ana Martínez10Ana Martínez11Alicia Mansilla12Alicia Mansilla13Department of Genetics, Institute of Ecology and Biodiversity (IEB), Faculty of Sciences, Universidad de Chile, Santiago, ChileFRAXA-DVI, FRAXA Research Foundation, Santiago, ChileDepartment of Neurobiology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, SpainDepartment of Neurobiology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, SpainDepartment of Neurobiology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, SpainDepartment of Immunology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, SpainCentro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainInstituto de Química-Física Rocasolano, Spanish National Research Council, Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, SpainCentro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Neurobiology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, SpainDepartment of Biology Systems, Universidad de Alcala, Madrid, SpainFragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability in situ and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker.https://www.frontiersin.org/articles/10.3389/fnins.2022.1007531/fullFragile X syndromeNcs-1Ric8adopamineprotein-protein interaction inhibitorFmr1 knockout |
| spellingShingle | Patricia Cogram Patricia Cogram Luis C. Fernández-Beltrán María José Casarejos Sonia Sánchez-Yepes Eulalia Rodríguez-Martín Alfonso García-Rubia Alfonso García-Rubia María José Sánchez-Barrena Carmen Gil Ana Martínez Ana Martínez Alicia Mansilla Alicia Mansilla The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes Frontiers in Neuroscience Fragile X syndrome Ncs-1 Ric8a dopamine protein-protein interaction inhibitor Fmr1 knockout |
| title | The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes |
| title_full | The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes |
| title_fullStr | The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes |
| title_full_unstemmed | The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes |
| title_short | The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes |
| title_sort | inhibition of ncs 1 binding to ric8a rescues fragile x syndrome mice model phenotypes |
| topic | Fragile X syndrome Ncs-1 Ric8a dopamine protein-protein interaction inhibitor Fmr1 knockout |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.1007531/full |
| work_keys_str_mv | AT patriciacogram theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT patriciacogram theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT luiscfernandezbeltran theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT mariajosecasarejos theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT soniasanchezyepes theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT eulaliarodriguezmartin theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT alfonsogarciarubia theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT alfonsogarciarubia theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT mariajosesanchezbarrena theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT carmengil theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT anamartinez theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT anamartinez theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT aliciamansilla theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT aliciamansilla theinhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT patriciacogram inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT patriciacogram inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT luiscfernandezbeltran inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT mariajosecasarejos inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT soniasanchezyepes inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT eulaliarodriguezmartin inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT alfonsogarciarubia inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT alfonsogarciarubia inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT mariajosesanchezbarrena inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT carmengil inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT anamartinez inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT anamartinez inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT aliciamansilla inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes AT aliciamansilla inhibitionofncs1bindingtoric8arescuesfragilexsyndromemicemodelphenotypes |