RESUMO
The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer's disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure [18F]-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression.
RESUMO
Fibroblast growth factor 1 (FGF1) is induced during myoblast differentiation at both transcriptional and translational levels. Here, we identify hnRNPM and p54nrb/NONO present in protein complexes bound to the FGF1 promoter and to the mRNA internal ribosome entry site (IRES). Knockdown or overexpression of these proteins indicate that they cooperate in activating IRES-dependent translation during myoblast differentiation, in a promoter-dependent manner. Importantly, mRNA transfection and promoter deletion experiments clearly demonstrate the impact of the FGF1 promoter on the activation of IRES-dependent translation via p54nrb and hnRNPM. Accordingly, knockdown of either p54 or hnRNPM also blocks endogenous FGF1 induction and myotube formation, demonstrating the physiological relevance of this mechanism and the role of these two proteins in myogenesis. Our study demonstrates the cooperative function of hnRNPM and p54nrb as regulators of IRES-dependent translation and indicates the involvement of a promoter-dependent mechanism.
Assuntos
Fator 1 de Crescimento de Fibroblastos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , Sítios Internos de Entrada Ribossomal , Mioblastos/citologia , Proteínas Associadas à Matriz Nuclear/metabolismo , Fatores de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas , Biossíntese de Proteínas , Proteínas de Ligação a RNA/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Proteínas de Ligação a DNA , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Camundongos , Mioblastos/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Fatores de Transcrição de Octâmero/genética , Ligação Proteica , Mapeamento de Interação de Proteínas , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Fibroblast growth factor 1 (FGF1) is involved in muscle development and regeneration. The FGF1 gene contains four tissue-specific promoters allowing synthesis of four transcripts with distinct leader regions. Two of these transcripts contain internal ribosome entry sites (IRESs), which are RNA elements allowing mRNA translation to occur in conditions of blockade of the classical cap-dependent mechanism. Here, we investigated the function and the regulation of FGF1 during muscle differentiation and regeneration. Our data show that FGF1 protein expression is induced in differentiating myoblasts and regenerating mouse muscle, whereas siRNA knock-down demonstrated FGF1 requirement for myoblast differentiation. FGF1 induction occurred at both transcriptional and translational levels, involving specific activation of both promoter A and IRES A, whereas global cap-dependent translation was inhibited. Furthermore, we identified, in the FGF1 promoter A distal region, a cis-acting element able to activate the IRES A-driven translation. These data revealed a mechanism of molecular coupling of mRNA transcription and translation, involving a unique process of IRES activation by a promoter element. The crucial role of FGF1 in myoblast differentiation provides physiological relevance to this novel mechanism. This finding also provides a new insight into the molecular mechanisms linking different levels of gene expression regulation.
