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

Ze’ev Melamed, Jone López-Erauskin, Michael W. Baughn, Ouyang Zhang, Kevin Drenner, Ying Sun, Fernande Freyermuth, Moira A. McMahon, Melinda S. Beccari, Jon W. Artates, Takuya Ohkubo, Maria Rodriguez, Nianwei Lin, Dongmei Wu, C. Frank Bennett, Frank Rigo, Sandrine Da Cruz, John Ravits, Clotilde Lagier-Tourenne, Don W. Cleveland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

242 Scopus citations

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.

Original languageAmerican English
Pages (from-to)180-190
Number of pages11
JournalNature Neuroscience
Volume22
Issue number2
DOIs
StatePublished - 1 Feb 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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