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Nat Neurosci. 2019 Feb;22(2):167-179. doi: 10.1038/s41593-018-0300-4. Epub 2019 Jan 14.

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

Klim JR1,2,3,4, Williams LA1,2,3,4,5, Limone F1,2,3,4,6, Guerra San Juan I1,2,3,4,7, Davis-Dusenbery BN1,2,3,4,8, Mordes DA1,2,3,4,9, Burberry A1,2,3,4, Steinbaugh MJ10, Gamage KK1,2,3,4,11, Kirchner R10, Moccia R1,2,3,4,12, Cassel SH1,2,3,4,13,14, Chen K15, Wainger BJ15,16, Woolf CJ15, Eggan K17,18,19,20.

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
2
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
3
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
4
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Q-State Biosciences, Cambridge, MA, USA.
6
Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
7
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
8
Seven Bridges Genomics, Cambridge, MA, USA.
9
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
10
Harvard T. H. Chan School of Public Health, Boston, MA, USA.
11
Amgen Research, Amgen, Inc., Cambridge, MA, USA.
12
Pfizer, Inc., Cambridge, MA, USA.
13
Harvard Medical School, Boston, MA, USA.
14
Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA.
15
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
16
Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
17
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. eggan@mcb.harvard.edu.
18
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. eggan@mcb.harvard.edu.
19
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. eggan@mcb.harvard.edu.
20
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eggan@mcb.harvard.edu.

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.

PMID:
30643292
DOI:
10.1038/s41593-018-0300-4

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