RESUMO
We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase ß. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polß(+/-) mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.
Assuntos
Doença de Alzheimer/patologia , DNA Polimerase beta/genética , Reparo do DNA , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose , Autofagia , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Heterozigoto , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Fenótipo , TranscriptomaRESUMO
Homology models are increasingly used to determine structural and functional relationships of genes and proteins in biomedical research. In the current study, for the first time, we compared the TRPC6 gene in mouse and human. The protein encoded by this gene forms a receptor activated calcium channel in cell membrane. Defects in this gene have been implicated in a wide range of diseases including glioblastomas. To determine the structural similarities in mouse and human TRPC6, we used standard bioinformatics tools such as fold prediction to identify the protein 3D structure, sequence-structure comparison, and prediction of template and protein structure. We also used glioblastoma cell line U373MG and human glioblastoma tumour tissues to study the expression of TRPC6 in disease conditions to implicate this gene in pathological ailment. Based on the results we conclude that human TRPC6 contains 90% identity and 93% similarity with mouse TRPC6, suggesting that this protein is well conserved in these two species. These isoforms likely demonstrate similar mechanisms in regulating gene expression; thus TRPC6 studies in mice may be extrapolated to humans.
Assuntos
Canais de Cátion TRPC/genética , Algoritmos , Sequência de Aminoácidos , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Biologia Computacional/métodos , Simulação por Computador , Glioblastoma/metabolismo , Humanos , Imageamento Tridimensional , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Isoformas de Proteínas/genética , Estrutura Secundária de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Software , Canal de Cátion TRPC6RESUMO
CREB3L4 is a member of the CREB/ATF transcription factor family, characterized by their regulation of gene expression through the cAMP-responsive element. Previous studies identified this protein in mice and humans. Whereas CREB3L4 in mice (referred to as Tisp40) is found in the testes and functions in spermatogenesis, human CREB3L4 is primarily detected in the prostate and has been implicated in cancer. We conducted computational analyses to compare the structural homology between murine Tisp40α human CREB3L4. Our results reveal that the primary and secondary structures of the two proteins contain high similarity. Additionally, predicted helical transmembrane structure reveals that the proteins likely have similar structure and function. This study offers preliminary findings that support the translation of mouse Tisp40α findings into human models, based on structural homology.