Disrupted in schizophrenia 1 (DISC1): regulation of the neuropeptide VGF and role in neurodevelopment and synapses
Por favor, use este identificador para citas ou ligazóns a este ítem:
http://hdl.handle.net/10347/13621
Ficheiros no ítem
Metadatos do ítem
Título: | Disrupted in schizophrenia 1 (DISC1): regulation of the neuropeptide VGF and role in neurodevelopment and synapses |
Autor/a: | Rodríguez Seoane, Carmen |
Dirección/Titoría: | Rodríguez Requena, Jesús |
Outro/a autor/a: | Universidade de Santiago de Compostela. Facultade de Medicina e Odontoloxía. Departamento de Medicina. Center for Research in Molecular Medicine and Chronic Disease (CIMUS) |
Palabras chave: | Esquizofrenia | Trastorno bipolar | Depresión | DISC1 | |
Data: | 2015-09-28 |
Resumo: | Since Disrupted in schizophrenia 1 (Disc1) was discovered, it has become one of the most convincing risk genes for major mental illness. Disc1 was first identified in a large Scottish family in which a genomic translocation affecting this gene cosegregated with major psychiatric diseases including schizophrenia, major depression and bipolar disorder. The protein encoded (DISC1) is highly expressed in the brain and, to date, no evidence of enzymatic activity has been reported. However, DISC1 binds more than 200 different proteins and acts as a molecular scaffold regulating the activity of such proteins. Thus, through these interactions, DISC1 participates in several processes in the brain such as neuronal proliferation, migration and differentiation as well as neurite outgrowth and synapse regulation. In order to gain new insight into the functions of DISC1, knock-down of the protein was performed in primary cortex and hippocampus mouse neurons as well as in the human neuroblastoma SH-SY5Y cell line by means of infection with small hairpin RNA (shRNA)-carrying lentivirus. In the present study DISC1 knock-down was found to lead to an important decrease in the levels of the neuropeptide VGF (non-acronymic) in SH-SY5Y as well as in primary cortical and hippocampal mouse neurons. Of note, VGF displays antidepressant properties and has been also shown to be implicated in different neuropsychiatric disorders including depression, bipolar disorder and schizophrenia. The fall of VGF levels produced by DISC1 knock-down seems to be mediated by a drop in the activity of the PI3K/AKT/CREB signaling as indicated by decreased levels of the active forms of AKT and CREB. Additionally, a decline in the levels of Grb2, an essential protein for PI3K activation and the subsequent signaling route, was observed in SH-SY5Y cells. In addition, knock-down of DISC1 was found to result in changes in the quantity and phosphorylation of GSK3β in primary mouse neurons suggesting the deregulation of the activity of the kinase. Furthermore, by means of a proteomic approach, the knock-down of DISC1 was observed to cause the differential regulation of a number of proteins in primary mouse neurons. Twelve of the proteins affected by the lack of DISC1 are involved in neurodevelopment and twelve participate in different aspects of the synapses. Of note, seven of these proteins share functions in both processes. Some of these proteins are known DISC1 binding partners; however, this is the first time that their expression is described to be dependent on DISC1. Supporting a role for DISC1 in neurodevelopment, its knock-down also produced deficits in the neurite outgrowth in SH-SY5Y cells treated with retinoic acid to induce their differentiation. The DISC1-VGF connection showed in the present study might be important for the development of new therapies for the treatment of mental diseases. In addition, the results show a new mechanism by which DISC1 regulates the activity of several proteins in neurons through the regulation of their levels. |
URI: | http://hdl.handle.net/10347/13621 |
Dereitos: | Esta obra atópase baixo unha licenza internacional Creative Commons BY-NC-ND 4.0. Calquera forma de reprodución, distribución, comunicación pública ou transformación desta obra non incluída na licenza Creative Commons BY-NC-ND 4.0 só pode ser realizada coa autorización expresa dos titulares, salvo excepción prevista pola lei. Pode acceder Vde. ao texto completo da licenza nesta ligazón: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.gl |
Coleccións
-
- Área de Ciencias da Saúde [1262]
A licenza do ítem descríbese como
Esta obra atópase baixo unha licenza internacional Creative Commons BY-NC-ND 4.0. Calquera forma de reprodución, distribución, comunicación pública ou transformación desta obra non incluída na licenza Creative Commons BY-NC-ND 4.0 só pode ser realizada coa autorización expresa dos titulares, salvo excepción prevista pola lei. Pode acceder Vde. ao texto completo da licenza nesta ligazón: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.gl
Esta obra atópase baixo unha licenza internacional Creative Commons BY-NC-ND 4.0. Calquera forma de reprodución, distribución, comunicación pública ou transformación desta obra non incluída na licenza Creative Commons BY-NC-ND 4.0 só pode ser realizada coa autorización expresa dos titulares, salvo excepción prevista pola lei. Pode acceder Vde. ao texto completo da licenza nesta ligazón: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.gl