Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS.
Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS.
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DOI：
10.1038/s41598-018-32902-4
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发表时间：
2018-10-03
影响因子：
4.6
通讯作者：
Ozdinler PH
中科院分区：
文献类型：
--
作者：
Dervishi I;Gozutok O;Murnan K;Gautam M;Heller D;Bigio E;Ozdinler PH
为神经退行性疾病开发有效的治疗策略需要了解导致神经元脆弱性和进行性变性的潜在细胞通路。迄今为止，147个不同基因中的许多突变被鉴定为与肌萎缩性侧索硬化症（ALS）“相关”、“修饰”或“致病”。这些基因的蛋白产物及其相互作用有助于确定ALS的蛋白质景观，并揭示了上游调节剂，关键的经典途径，相互作用域和新的治疗靶点。我们的分析源于已知的人类突变，并回到人类，揭示了在sALS患者和TDP 43病理患者的贝茨细胞中PPARG和PPARGC 1A表达增加，并强调了脂质稳态的重要性。YWHAZ（一种14-3-3蛋白）的下调和ZFYVE 27的细胞质积累（特别是在ALS患者的患病贝茨细胞中）强化了以下观点：扰乱的蛋白质通讯、相互作用组缺陷和改变的会聚途径将揭示ALS中的新治疗靶点。
Developing effective treatment strategies for neurodegenerative diseases require an understanding of the underlying cellular pathways that lead to neuronal vulnerability and progressive degeneration. To date, numerous mutations in 147 distinct genes are identified to be “associated” with, “modifier” or “causative” of amyotrophic lateral sclerosis (ALS). Protein products of these genes and their interactions helped determine the protein landscape of ALS, and revealed upstream modulators, key canonical pathways, interactome domains and novel therapeutic targets. Our analysis originates from known human mutations and circles back to human, revealing increased PPARG and PPARGC1A expression in the Betz cells of sALS patients and patients with TDP43 pathology, and emphasizes the importance of lipid homeostasis. Downregulation of YWHAZ, a 14-3-3 protein, and cytoplasmic accumulation of ZFYVE27 especially in diseased Betz cells of ALS patients reinforce the idea that perturbed protein communications, interactome defects, and altered converging pathways will reveal novel therapeutic targets in ALS.
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