RESUMO
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
Assuntos
Apolipoproteínas E , Demência Frontotemporal , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas tau , Humanos , Demência Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Feminino , Idoso , Polimorfismo de Nucleotídeo Único , Loci Gênicos , Pessoa de Meia-Idade , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
Insulin-like peptide 3 (INSL3) is a biomarker for Leydig cells in the testes of vertebrates, and it is principally involved in spermatogenesis through specific binding with the RXFP2 receptor. This study reports the insl3 gene transcript and the Insl3 prepropeptide expression in both non-reproductive and reproductive tissues of Danio rerio. An immunohistochemistry analysis shows that the hormone is present at a low level in the Leydig cells and germ cells at all stages of Danio rerio testis differentiation. Considering that the insl3 gene is transcribed in Leydig cells, our results highlight an autocrine and paracrine function of this hormone in the Danio rerio testis, adding new information on the Insl3 mode of action in reproduction. We also show that Insl3 and Rxfp2 belonging to Danio rerio and other vertebrate species share most of the amino acid residues involved in the ligand-receptor interaction and activation, suggesting a conserved mechanism of action during vertebrate evolution.
Assuntos
Insulinas , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Masculino , Sequência de Aminoácidos , Insulinas/metabolismo , Insulinas/genética , Células Intersticiais do Testículo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Espermatogênese/genética , Testículo/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Neuronal gene expression in the brain dynamically responds to synaptic activity. The interplay among synaptic activity, gene expression, and synaptic plasticity has crucial implications for understanding the pathophysiology of diseases such as Alzheimer's disease and epilepsy. These diseases are marked by synaptic dysfunction that affects the expression patterns of neuroprotective genes that are incompletely understood. In our study, we developed a cellular model of synaptic activity using human cholinergic neurons derived from SH-SY5Y cell differentiation. Depolarization induction modulates the expression of neurotrophic genes and synaptic markers, indicating a potential role in synaptic plasticity regulation. This hypothesis is further supported by the induction kinetics of various long non-coding RNAs, including primate-specific ones. Our experimental model showcases the utility of SH-SY5Y cells in elucidating the molecular mechanisms underlying synaptic plasticity in human cellular systems.