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

Evgeny Shlevkov; Himanish Basu; Mark-Anthony Bray; Zheng Sun; Wei Wei; Kaan Apaydin; Kyle Karhohs; Pin-Fang Chen; Janell L.M. Smith; Ole Wiskow; Kasper Roet; Xuan Huang; Kevin Eggan; Anne E. Carpenter; Robin J. Kleiman; Thomas L. Schwarz

Cell Reports (Sep 2019)

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

Evgeny Shlevkov,
Himanish Basu,
Mark-Anthony Bray,
Zheng Sun,
Wei Wei,
Kaan Apaydin,
Kyle Karhohs,
Pin-Fang Chen,
Janell L.M. Smith,
Ole Wiskow,
Kasper Roet,
Xuan Huang,
Kevin Eggan,
Anne E. Carpenter,
Robin J. Kleiman,
Thomas L. Schwarz

Affiliations

Evgeny Shlevkov: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Himanish Basu: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Mark-Anthony Bray: Imaging Platform, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Zheng Sun: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Wei Wei: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kaan Apaydin: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kyle Karhohs: Imaging Platform, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Pin-Fang Chen: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
Janell L.M. Smith: 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
Ole Wiskow: 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
Kasper Roet: 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
Xuan Huang: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kevin Eggan: 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
Anne E. Carpenter: Imaging Platform, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Robin J. Kleiman: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
Thomas L. Schwarz: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Corresponding author

Journal volume & issue: Vol. 28, no. 12
pp. 3224 – 3237.e5

Abstract

Read online

Summary: 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. : Shlevkov et al. establish a high-content screen for enhancers of axonal mitochondrial trafficking. Identified compounds act through three cellular targets: F-Actin, Tripeptidyl peptidase 1, and Aurora Kinase B. Motor neurons derived from a SOD1+/A4VALS patient have decreased mitochondrial motility, which can be reversed by inhibitors of these targets. Keywords: mitochondria, high-content screening, Aurora B, TPP1, F-actin, ALS, axonal transport

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal