Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain.
Proteored-ISCIII, Proteomics Platform, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain.
Int J Mol Sci. 2020 Nov 5;21(21):8311. doi: 10.3390/ijms21218311.
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive muscle paralysis due to the degeneration of upper and lower motor neurons. Recent studies point out an involvement of the non-motor axis during disease progression. Despite smell impairment being considered a potential non-motor finding in ALS, the pathobiochemistry at the olfactory level remains unknown. Here, we applied an olfactory quantitative proteotyping approach to analyze the magnitude of the olfactory bulb (OB) proteostatic imbalance in ALS subjects ( = 12) with respect to controls ( = 8). Around 3% of the quantified OB proteome was differentially expressed, pinpointing aberrant protein expression involved in vesicle-mediated transport, macroautophagy, axon development and gliogenesis in ALS subjects. The overproduction of olfactory marker protein () points out an imbalance in the olfactory signal transduction in ALS. Accompanying the specific overexpression of glial fibrillary acidic protein () and Bcl-xL in the olfactory tract (OT), a tangled disruption of signaling routes was evidenced across the OB-OT axis in ALS. In particular, the OB survival signaling dynamics clearly differ between ALS and frontotemporal lobar degeneration (FTLD), two faces of TDP-43 proteinopathy. To the best of our knowledge, this is the first report on high-throughput molecular characterization of the olfactory proteostasis in ALS.
肌萎缩侧索硬化症（ALS）是一种致命的疾病，其特征是由于上下运动神经元的退化导致肌肉进行性瘫痪。最近的研究指出，在疾病进展过程中存在非运动轴的参与。尽管嗅觉障碍被认为是 ALS 的一种潜在非运动表现，但嗅觉水平的病理生物化学仍不清楚。在这里，我们应用嗅觉定量蛋白质组学方法来分析 ALS 患者（n=12）与对照组（n=8）嗅球（OB）的蛋白质组平衡失衡的程度。约 3%的定量 OB 蛋白质组存在差异表达，指出 ALS 患者中涉及囊泡介导运输、巨自噬、轴突发育和神经胶质发生的异常蛋白表达。嗅觉标记蛋白（）的过度产生指出 ALS 中嗅觉信号转导的失衡。在嗅觉通路上，胶质纤维酸性蛋白（）和 Bcl-xL 的特异性过表达伴随着 OB-OT 轴上信号通路的缠结破坏，这在 ALS 中得到了证实。特别是，OB 存活信号动力学在 ALS 和额颞叶变性（FTLD）之间明显不同，TDP-43 蛋白病的两种表现。据我们所知，这是关于 ALS 嗅觉蛋白平衡的高通量分子特征的首次报道。
