STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43 Nuclear Depletion in ALS Motor Neurons

Loss of nuclear TDP-43 in ALS motor neurons first manifests as aberrant inclusion of the STMN2 cryptic exon 2a, producing a truncated non-functional STMN2 protein that impairs microtubule repair at the axon. This splicing defect precedes detectable cytoplasmic TDP-43 aggregation by at least 48h in iPSC motor neurons subjected to TDP-43 depletion, establishing STMN2 cryptic exon inclusion as the earliest measurable loss-of-function event. Restoring STMN2 function with antisense oligonucleotides should delay axonal degeneration even when cytoplasmic aggregates have already formed.