HSCI Retreat 2019 Abstract 1

ABSTRACT

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as an ALS disease mechanism. The RNAs regulated by TDP-43 in human motor neurons and their connection to neuropathy, however, remain to be identified. Using human pluripotent stem cell technologies and RNA sequencing, we identified transcripts whose abundances in motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. These findings were enabled by human pluripotent stem cell disease modeling as this regulation of STMN2 by TDP-43 is not found in mice. When we knock Stmn2 out in mice, however, the animals develop motor deficits. Based on our findings, we propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.