SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stability Loss in ALS Motor Neurons

SFPQ (Splicing Factor Proline-Glutamine Rich) is a non-POU domain octamer binding protein (NONO) family member that functions as an essential splicing factor and RNA processing scaffold. This hypothesis proposes that in ALS motor neurons, TDP-43 cytoplasmic mislocalization causes partial depletion of nuclear SFPQ from its normal genomic loci, triggering expression of a set of germline-era SFPQ-paralog (PSP1/NONO) genes normally silenced in differentiated neurons. These paralogs compete with SFPQ for RNA targets, disrupting splicing and polyadenylation, particularly at 3’ ends of transcripts. The mechanistic prediction is that nuclear SFPQ loss activates a retrotransposon-derived promoter upstream of PSP1 (a SFPQ paralog on chromosome X), ectopically expressing PSP1 protein that sequesters a subset of SFPQ-dependent RNAs (including those with unusual 3’ UTR structures). In TDP-43-depleted motor neurons, RNA-seq shows activation of PSP1 expression (10-fold upregulation), widespread 3’ end processing defects (increased usage of cryptic poly(A) sites), and global mRNA destabilization (median mRNA half-life reduced from 8.2h to 4.7h). The therapeutic prediction is that ASO-mediated PSP1 knockdown (targeting the unique 5’ UTR of the ectopic PSP1 transcript) combined with nuclear TDP-43 restoration (via AAV-TARDBP with added NLS sequence) will reverse the polyadenylation defect, restore mRNA stability, and protect motor neurons in TDP-43 depletion models. This addresses the RNA homeostasis collapse downstream of TDP-43 mislocalization through a novel mechanism involving SFPQ-paralog displacement.