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

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.

LanguageEnglish
Pages167-179
Number of pages13
JournalNature Neuroscience
Volume22
Issue number2
Early online date14 Jan 2019
DOIs
Publication statusPublished - Feb 2019

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Amyotrophic Lateral Sclerosis
Motor Neurons
Regeneration
Growth
RNA
Proteins
RNA-Binding Proteins
Microtubules
Axons
Spinal Cord
Mutation
Genes
Therapeutics

Cite this

Klim, J. R., Williams, L. A., Limone, F., Guerra San Juan, I., Davis-Dusenbery, B. N., Mordes, D. A., ... Eggan, K. (2019). ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nature Neuroscience, 22(2), 167-179. https://doi.org/10.1038/s41593-018-0300-4
Klim, Joseph R. ; Williams, Luis A. ; Limone, Francesco ; Guerra San Juan, Irune ; Davis-Dusenbery, Brandi N. ; Mordes, Daniel A. ; Burberry, Aaron ; Steinbaugh, Michael J. ; Gamage, Kanchana K. ; Kirchner, Rory ; Moccia, Rob ; Cassel, Seth H. ; Chen, Kuchuan ; Wainger, Brian J. ; Woolf, Clifford J. ; Eggan, Kevin. / ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. In: Nature Neuroscience. 2019 ; Vol. 22, No. 2. pp. 167-179.
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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.",
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Klim, JR, Williams, LA, Limone, F, Guerra San Juan, I, Davis-Dusenbery, BN, Mordes, DA, Burberry, A, Steinbaugh, MJ, Gamage, KK, Kirchner, R, Moccia, R, Cassel, SH, Chen, K, Wainger, BJ, Woolf, CJ & Eggan, K 2019, 'ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair', Nature Neuroscience, vol. 22, no. 2, pp. 167-179. https://doi.org/10.1038/s41593-018-0300-4

ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. / Klim, Joseph R.; Williams, Luis A.; Limone, Francesco; Guerra San Juan, Irune; Davis-Dusenbery, Brandi N.; Mordes, Daniel A.; Burberry, Aaron; Steinbaugh, Michael J.; Gamage, Kanchana K.; Kirchner, Rory; Moccia, Rob; Cassel, Seth H.; Chen, Kuchuan; Wainger, Brian J.; Woolf, Clifford J.; Eggan, Kevin.

In: Nature Neuroscience, Vol. 22, No. 2, 02.2019, p. 167-179.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Klim, Joseph R.

AU - Williams, Luis A.

AU - Limone, Francesco

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AU - Davis-Dusenbery, Brandi N.

AU - Mordes, Daniel A.

AU - Burberry, Aaron

AU - Steinbaugh, Michael J.

AU - Gamage, Kanchana K.

AU - Kirchner, Rory

AU - Moccia, Rob

AU - Cassel, Seth H.

AU - Chen, Kuchuan

AU - Wainger, Brian J.

AU - Woolf, Clifford J.

AU - Eggan, Kevin

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