Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration.
Ze'ev MelamedJone López-ErauskinMichael W BaughnOuyang ZhangKevin DrennerYing SunFernande FreyermuthMoira A McMahonMelinda S BeccariJon W ArtatesTakuya OhkuboMaria RodriguezNianwei LinDongmei WuC Frank BennettFrank RigoSandrine Da CruzJohn RavitsClotilde Lagier-TourenneDon W ClevelandPublished in: Nature neuroscience (2019)
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.
Keyphrases
- amyotrophic lateral sclerosis
- binding protein
- stem cells
- spinal cord
- poor prognosis
- spinal cord injury
- gene expression
- mesenchymal stem cells
- bone marrow
- dna methylation
- case report
- early onset
- genome wide
- circulating tumor
- copy number
- brain injury
- drug induced
- late onset
- endothelial cells
- cell free
- extracellular matrix
- genome wide analysis
- blood brain barrier
- optic nerve
- subarachnoid hemorrhage