Palluzzi Fernando, Ferrari Raffaele, Graziano Francesca, Novelli Valeria, Rossi Giacomina, Galimberti Daniela, Rainero Innocenzo, Benussi Luisa, Nacmias Benedetta, Bruni Amalia C, Cusi Daniele, Salvi Erika, Borroni Barbara, Grassi Mario
Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
Department of Molecular Neuroscience, Institute of Neurology, University College London (UCL), London, United Kingdom.
PLoS One. 2017 Oct 11;12(10):e0185797. doi: 10.1371/journal.pone.0185797. eCollection 2017.
Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.
额颞叶痴呆（FTD）是仅次于阿尔茨海默病的最常见的神经退行性痴呆形式，在男性和女性中分布均匀。它包括几种变体，通常表现为行为不稳定和语言障碍。虽然少数孟德尔基因（MAPT、GRN和C9orf72）与FTD表型相关，但在大多数情况下，仅有证据表明存在多个效应大小相对较小的风险基因座。迄今为止，尚无在分子水平描述FTD的全面研究，以突出FTD相关神经退行性变起源时可能的基因相互作用和信号通路。在本研究中，我们通过一种基于疾病相关性和相互作用扰动概念的新型网络方法，结合斯坦纳树搜索和结构方程模型（SEM）分析，设计了意大利人群的广泛FTD基因相互作用图谱。我们的结果表明钙/环磷酸腺苷代谢、氧化应激诱导的丝氨酸/苏氨酸激酶激活与突触后膜增强之间存在密切联系，提示可能存在神经元损伤和神经保护丧失的组合，导致细胞死亡。在我们的模型中，钙/环磷酸腺苷稳态和能量代谢受损分别是神经保护丧失和神经细胞损伤的主要原因。其次，应激诱导的丝氨酸/苏氨酸激酶激活导致的突触后膜增强改变会导致神经退行性变。我们的研究调查了这些过程的分子基础，证明了关键基因和基因相互作用可能占未解释的FTD病因的很大一部分。我们强调了这些过程中的关键分子参与者，将它们作为新型FTD生物标志物提出，这可能对进一步的流行病学和分子研究至关重要。
