ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
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-...
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| Published in | Nature neuroscience Vol. 22; no. 2; pp. 167 - 179 |
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| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.02.2019
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Summary: | 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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present addresses: Q-State Biosciences, Cambridge, MA, USA (L.A.W.); Seven Bridges Genomics, Cambridge, MA, USA (B.N.D.); Pfizer Inc., Cambridge, MA 02139 (R.M.); Harvard Medical School, Boston, MA 02115 (S.C.); Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA. (B.J.W.); Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA (S.H.C). Author Contributions L.A.W., B.N.D. K.E. conceived the approach for identifying hMN RNA targets of TDP-43. L.A.W., B.N.D. performed siRNA experiments; J.R.K., F.L. performed iPSC and proteostasis studies; L.A.W. and I.G.S.J. characterized STMN2 expression in neurons with S.H.C.; J.R.K., M.J.S., B.N.D., R.D.K., and R.M. analyzed RNA-Seq and microarray data; J.R.K. and I.G.S.J. generated STMN2 knockouts; I.G.S.J. performed outgrowth and regrowth assays with support from J.R.K., F.L., and K.G.; J.R.K., L.A.W. and A.B. developed the cell surface profile to sort neurons; D.A.M. collected the post-mortem samples and performed immunohistochemistry; K.C., B.J.W. performed electrophysiological recordings with support from C.J.W.. J.R.K. and L.A.W. contributed equally to the manuscript, and F.L. and I.G.S.J. contributed equally to these studies. J.R.K., L.A.W., K.E. wrote the manuscript; K.E. supervised all aspects of the study. All authors reviewed and edited this manuscript. |
| ISSN: | 1097-6256 1546-1726 1546-1726 |
| DOI: | 10.1038/s41593-018-0300-4 |