高内涵筛选鉴定 TPP1 和 Aurora B 为轴突线粒体运输的调节因子。
A High-Content Screen Identifies TPP1 and Aurora B as Regulators of Axonal Mitochondrial Transport.
机构信息
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Imaging Platform, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
出版信息
Cell Rep. 2019 Sep 17;28(12):3224-3237.e5. doi: 10.1016/j.celrep.2019.08.035.
Dysregulated axonal trafficking of mitochondria is linked to neurodegenerative disorders. We report a high-content screen for small-molecule regulators of the axonal transport of mitochondria. Six compounds enhanced mitochondrial transport in the sub-micromolar range, acting via three cellular targets: F-actin, Tripeptidyl peptidase 1 (TPP1), or Aurora Kinase B (AurKB). Pharmacological inhibition or small hairpin RNA (shRNA) knockdown of each target promotes mitochondrial axonal transport in rat hippocampal neurons and induced pluripotent stem cell (iPSC)-derived human cortical neurons and enhances mitochondrial transport in iPSC-derived motor neurons from an amyotrophic lateral sclerosis (ALS) patient bearing one copy of SOD1 mutation. Our work identifies druggable regulators of axonal transport of mitochondria, provides broadly applicable methods for similar image-based screens, and suggests that restoration of proper axonal trafficking of mitochondria can be achieved in human ALS neurons.
线粒体的轴突运输失调与神经退行性疾病有关。我们报告了一种用于筛选线粒体轴突运输小分子调节剂的高通量筛选方法。六种化合物以亚微摩尔范围增强线粒体的运输，通过三种细胞靶标起作用：F-肌动蛋白、三肽基肽酶 1（TPP1）或 Aurora 激酶 B（AurKB）。每个靶标的药理学抑制或短发夹 RNA（shRNA）敲低均可促进大鼠海马神经元、诱导多能干细胞（iPSC）衍生的人类皮质神经元中线粒体的轴突运输，并增强携带 SOD1 突变的肌萎缩性侧索硬化症（ALS）患者 iPSC 衍生的运动神经元中线粒体的运输。我们的工作确定了线粒体轴突运输的可药物调节因子，为类似的基于图像的筛选提供了广泛适用的方法，并表明在人类 ALS 神经元中可以实现线粒体的适当轴突运输的恢复。
Zotero 插件