Format

Send to

Choose Destination
Nat Neurosci. 2019 Feb;22(2):180-190. doi: 10.1038/s41593-018-0293-z. Epub 2019 Jan 14.

Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration.

Author information

1
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
2
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
3
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
4
Broad Institute of Harvard University and MIT, Cambridge, MA, USA.
5
Ionis Pharmaceuticals, Carlsbad, CA, USA.
6
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
7
iXCells Biotechnologies, San Diego, CA, USA.
8
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. clagier-tourenne@mgh.harvard.edu.
9
Broad Institute of Harvard University and MIT, Cambridge, MA, USA. clagier-tourenne@mgh.harvard.edu.
10
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA. dcleveland@ucsd.edu.
11
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA. dcleveland@ucsd.edu.
12
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. dcleveland@ucsd.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.

PMID:
30643298
PMCID:
PMC6348009
[Available on 2019-07-14]
DOI:
10.1038/s41593-018-0293-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center