ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

Joseph R. Klim, Luis A. Williams, Francesco Limone, Irune Guerra San Juan, Brandi N. Davis-Dusenbery, Daniel A. Mordes, Aaron Burberry, Michael J. Steinbaugh, Kanchana K. Gamage, Rory Kirchner, Rob Moccia, Seth H. Cassel, Kuchuan Chen, Brian J. Wainger, Clifford J. Woolf, Kevin Eggan*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.

Original languageEnglish
Pages (from-to)167-179
Number of pages13
JournalNature Neuroscience
Volume22
Issue number2
Early online date14 Jan 2019
DOIs
Publication statusPublished - Feb 2019

Fingerprint Dive into the research topics of 'ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair'. Together they form a unique fingerprint.

Cite this