Journal
NATURE NEUROSCIENCE
Volume 22, Issue 2, Pages 180-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0293-z
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Funding
- NINDS/NIH [R01-NS27036, R01-NS087227, R01-NS088578]
- Target ALS [S20A00]
- Muscular Dystrophy Association (MDA)
- EMBO long-term fellowship
- Human Frontiers Science Program (HFSP) long-term fellowship
- Milton Safenowitz postdoctoral fellowship
- National Institute of General Medical Sciences of the National Institutes of Health [T32-GM008666]
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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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