Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, USA.
Mesulam Cognitive Neurology and Alzheimer Disease Center, Chicago, IL, 60611, USA.
Sci Rep. 2018 Oct 3;8(1):14732. doi: 10.1038/s41598-018-32902-4.
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.
开发针对神经退行性疾病的有效治疗策略需要了解导致神经元易损性和进行性退化的潜在细胞途径。迄今为止，已鉴定出 147 个不同基因中的许多突变与肌萎缩侧索硬化症 (ALS)“相关”、“修饰”或“致病”。这些基因的蛋白质产物及其相互作用有助于确定 ALS 的蛋白质图谱，并揭示了上游调节剂、关键经典途径、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，并回归到人类，揭示了 sALS 患者和具有 TDP43 病理学的患者的贝茨细胞中 PPARG 和 PPARGC1A 的表达增加，强调了脂质动态平衡的重要性。YWHAZ（一种 14-3-3 蛋白）的下调和 ZFYVE27 的细胞质积累，特别是在 ALS 患者的患病贝茨细胞中，加强了这样一种观点，即受干扰的蛋白质通讯、相互作用缺陷和改变的汇聚途径将在 ALS 中揭示新的治疗靶点。
