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

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

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