Hale Oliver J, Wells Tyler R, Mead Richard J, Cooper Helen J
School of Biosciences, University of Birmingham, Birmingham, UK.
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Nat Commun. 2024 Aug 8;15(1):6518. doi: 10.1038/s41467-024-50514-7.
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1 complexes in SOD1 transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1 species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1 species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.
肌萎缩侧索硬化症（ALS）的特征是中枢神经系统（CNS）中的运动神经元退化。金属酶超氧化物歧化酶1（SOD1）的突变与遗传性ALS相关，会导致功能毒性增强，这种毒性增强被认为是由二聚体不稳定和错误折叠介导的。SOD1以同源二聚体形式结合两个铜离子和两个锌离子。我们应用原位常压质谱成像技术来可视化SOD1转基因小鼠脊髓和脑切片中完整的金属结合SOD1复合物的空间分布，并根据疾病病理学对其进行评估。我们方法的分子特异性表明，金属缺乏的SOD1种类在与ALS病理学相关的CNS结构中含量丰富，而完全金属化的SOD1种类则均匀分布。单体丰度与病理学无关。我们还表明，使二聚体不稳定的翻译后修饰——谷胱甘肽化，对SOD1二聚体的空间分布影响有限。
