RNA processing alteration and the link to neurodegeneration

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear RNA-binding protein TDP-43. Given the central role of TDP-43 in RNA metabolism, it is anticipated that nuclear clearance of TDP-43 drives processing alterations of multiple RNAs in affected neurons of ALS/FTD patients. However, a direct link to increased neuronal vulnerability from reduction or mutation in TDP-43 remains unclear. Here, we have identified a critical role for TDP-43 in regulating expression of stathmin-2, a microtubule-associated protein essential for axon stability and regeneration. Reduction of TDP-43 suppresses stathmin-2 levels by uncovering a premature polyadenylation site in stathmin-2 pre-mRNA, producing a short non-functional mRNA.

Suppression of stathmin-2 encoding mRNA is found in neurons trans-differentiated from patient fibroblasts carrying an ALS-causing TDP-43 mutation and in iPSC-derived motor neurons depleted of TDP-43. Remarkably, premature polyadenylation of stathmin-2 is consistently found in motor cortex and spinal motor neurons isolated from sporadic ALS patients. Finally, we show that lowering TDP-43 or stathmin-2 impairs the ability of iPSC-derived motor neurons to regenerate. Restoration of stathmin-2 levels rescues axonal regeneration capacity in the absence of TDP-43, evidence supporting stathmin-2 as a potential therapeutic target in neurodegenerative diseases—especially ALS and FTD—affected by TDP-43 proteinopathy.