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

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 i...

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Published in:Nature neuroscience 2019-02, Vol.22 (2), p.180-190
Main Authors: 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
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Binding proteins
Complications and side effects
Cortex (motor)
Dementia
Dementia disorders
Deoxyribonucleic acid
DNA
DNA-binding protein
DNA-Binding Proteins - metabolism
Female
Fibroblasts
Frontotemporal dementia
Gene expression
Gene mutation
Genes
Humans
Membrane Proteins - metabolism
Messenger RNA
Motor Cortex - metabolism
Motor Cortex - pathology
Motor neurons
Motor Neurons - metabolism
Motor Neurons - pathology
Motors
mRNA
Mutation
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neurodegeneration
Neurons
Pluripotency
Polyadenylation
Protein binding
Proteins
Reduction
Regeneration
Ribonucleic acid
RNA
Spinal Cord - metabolism
Spinal Cord - pathology
Stathmin
Stem cells
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Summary: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.
ISSN:1097-6256
1546-1726
DOI:10.1038/s41593-018-0293-z