Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea, 3, 31008 Pamplona, Spain; Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, Irunlarrea 3, 31008 Pamplona, Spain.
Translational Biomarker Group, Department of Human Protein Sciences, University of Geneva, Rue Michel Servet 1, 1211 Geneve 4, Switzerland.
J Proteomics. 2019 Jun 15;201:37-47. doi: 10.1016/j.jprot.2019.04.011. Epub 2019 Apr 15.
Mild olfactory dysfunction has been observed in frontotemporal dementias (FTD). However, the underlying molecular mechanisms associated to this deficit are poorly understood. We applied quantitative proteomics to analyze pathological effects on the olfactory bulb (OB) from progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTLD-TDP43) subjects respect to elderly non-FTD group. Our data revealed: i) a mitochondrial and calcium homeostasis impairment in PSP and ii) a disruption of protein synthesis and vesicle trafficking in FTLD-TDP43. Although differential OB proteomes clearly differ between both FTD phenotypes, functional analyses pointed out an imbalance in survival signaling in both pathologies. A common alteration of olfactory mitogen-activated protein kinases (MAPKs), calcium/calmodulin dependent protein kinase II (CAMKII), and protein kinase C (PKC) signaling pathways was observed in PSP and FTLD subjects. In contrast, a specific shut off in mitogen-activated protein kinase kinase 4 (SEK1/MKK4)/stress-activated protein kinase (SAPK) axis was exclusively observed in PSP, whereas a specific phosphoinositide-dependent protein kinase 1 (PDK1) inactivation was observed in FTLD-TDP43. In summary, our data contribute to a better understanding of the molecular mechanisms that are modulated in PSP and FTLD-TDP43 at olfactory level, highlighting cross-disease similarities and differences in the regulation of survival pathways across FTD spectrum. SIGNIFICANCE: This work reflects differential olfactory molecular disarrangements in PSP and FTLD-TDP43, two clinically similar FTD disorders, but with different neuropathological signature. Besides FTDs present mild olfactory dysfunction, our data provide basic information for understanding the implication of the OB in the pathophysiology of FTDs.
轻度嗅觉功能障碍已在额颞叶痴呆（FTD）中观察到。然而，与这种缺陷相关的潜在分子机制仍知之甚少。我们应用定量蛋白质组学分析了进行性核上性麻痹（PSP）和额颞叶变性（FTLD-TDP43）患者的嗅球（OB）的病理影响，与老年非 FTD 组进行比较。我们的数据显示：i）PSP 中存在线粒体和钙稳态受损，ii）FTLD-TDP43 中存在蛋白质合成和囊泡运输中断。尽管两种 FTD 表型的 OB 差异明显，但功能分析指出两种病理中存活信号失衡。在 PSP 和 FTLD 患者中观察到嗅觉有丝分裂原激活蛋白激酶（MAPKs）、钙/钙调蛋白依赖性蛋白激酶 II（CAMKII）和蛋白激酶 C（PKC）信号通路的共同改变。相反，在 PSP 中仅观察到有丝分裂原激活蛋白激酶激酶 4（SEK1/MKK4）/应激激活蛋白激酶（SAPK）轴的特异性关闭，而在 FTLD-TDP43 中仅观察到磷酸肌醇依赖性蛋白激酶 1（PDK1）的特异性失活。总之，我们的数据有助于更好地理解在 PSP 和 FTLD-TDP43 中调节的分子机制，强调了在 FTD 谱中跨疾病的存活途径调节的相似性和差异性。意义：这项工作反映了 PSP 和 FTLD-TDP43 两种在临床上相似的 FTD 疾病之间的嗅觉分子紊乱的差异，但具有不同的神经病理学特征。除了 FTD 患者存在轻度嗅觉功能障碍外，我们的数据为理解 OB 在 FTD 病理生理学中的作用提供了基础信息。
