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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 Sep 19

PMID 31533043

Citations 22

Authors

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

Soon will be listed here.

Abstract

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.

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