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

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Title: ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.
Authors: 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
Source: Nature Neuroscience. Feb2019, Vol. 22 Issue 2, p167-179. 13p. 1 Diagram, 7 Graphs.
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. Klim et al. illuminate pathomechanisms of ALS using pluripotent stem cells to identify transcripts altered in human motor neurons by perturbations to ALS protein TDP-43, finding the microtubule regulator STMN2 highly sensitive to TDP-43 malfunctions. [ABSTRACT FROM AUTHOR]
Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.
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  Data: <searchLink fieldCode="AR" term="%22Klim%2C+Joseph+R%2E%22">Klim, Joseph R.</searchLink><br /><searchLink fieldCode="AR" term="%22Williams%2C+Luis+A%2E%22">Williams, Luis A.</searchLink><br /><searchLink fieldCode="AR" term="%22Limone%2C+Francesco%22">Limone, Francesco</searchLink><br /><searchLink fieldCode="AR" term="%22Guerra+San+Juan%2C+Irune%22">Guerra San Juan, Irune</searchLink><br /><searchLink fieldCode="AR" term="%22Davis-Dusenbery%2C+Brandi+N%2E%22">Davis-Dusenbery, Brandi N.</searchLink><br /><searchLink fieldCode="AR" term="%22Mordes%2C+Daniel+A%2E%22">Mordes, Daniel A.</searchLink><br /><searchLink fieldCode="AR" term="%22Burberry%2C+Aaron%22">Burberry, Aaron</searchLink><br /><searchLink fieldCode="AR" term="%22Steinbaugh%2C+Michael+J%2E%22">Steinbaugh, Michael J.</searchLink><br /><searchLink fieldCode="AR" term="%22Gamage%2C+Kanchana+K%2E%22">Gamage, Kanchana K.</searchLink><br /><searchLink fieldCode="AR" term="%22Kirchner%2C+Rory%22">Kirchner, Rory</searchLink><br /><searchLink fieldCode="AR" term="%22Moccia%2C+Rob%22">Moccia, Rob</searchLink><br /><searchLink fieldCode="AR" term="%22Cassel%2C+Seth+H%2E%22">Cassel, Seth H.</searchLink><br /><searchLink fieldCode="AR" term="%22Chen%2C+Kuchuan%22">Chen, Kuchuan</searchLink><br /><searchLink fieldCode="AR" term="%22Wainger%2C+Brian+J%2E%22">Wainger, Brian J.</searchLink><br /><searchLink fieldCode="AR" term="%22Woolf%2C+Clifford+J%2E%22">Woolf, Clifford J.</searchLink><br /><searchLink fieldCode="AR" term="%22Eggan%2C+Kevin%22">Eggan, Kevin</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Nature+Neuroscience%22">Nature Neuroscience</searchLink>. Feb2019, Vol. 22 Issue 2, p167-179. 13p. 1 Diagram, 7 Graphs.
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  Data: 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. Klim et al. illuminate pathomechanisms of ALS using pluripotent stem cells to identify transcripts altered in human motor neurons by perturbations to ALS protein TDP-43, finding the microtubule regulator STMN2 highly sensitive to TDP-43 malfunctions. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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