例如："lncRNA", "apoptosis", "WRKY"

A High-Content Screen Identifies TPP1 and Aurora B as Regulators of Axonal Mitochondrial Transport.

Cell Rep. 2019 Sep 17;28(12):3224-3237.e5
Evgeny Shlevkov 1 , Himanish Basu 1 , Mark-Anthony Bray 2 , Zheng Sun 1 , Wei Wei 1 , Kaan Apaydin 1 , Kyle Karhohs 2 , Pin-Fang Chen 3 , Janell L M Smith 4 , Ole Wiskow 4 , Kasper Roet 5 , Xuan Huang 1 , Kevin Eggan 4 , Anne E Carpenter 2 , Robin J Kleiman 3 , Thomas L Schwarz 6
Evgeny Shlevkov 1 , Himanish Basu 1 , Mark-Anthony Bray 2 , Zheng Sun 1 , Wei Wei 1 , Kaan Apaydin 1 , Kyle Karhohs 2 , Pin-Fang Chen 3 , Janell L M Smith 4 , Ole Wiskow 4 , Kasper Roet 5 , Xuan Huang 1 , Kevin Eggan 4 , Anne E Carpenter 2 , Robin J Kleiman 3 , Thomas L Schwarz 6
+ et al

[No authors listed]

Author information
  • 1 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Imaging Platform, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • 3 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 5 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 6 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: thomas.schwarz@childrens.harvard.edu.

摘要

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 SOD1A4V 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. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

KEYWORDS: ALS, Aurora B, F-actin, TPP1, axonal transport, high-content screening, mitochondria

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