An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is upregulated in ALS

Splicing factor proline- and glutamine-rich (SFPQ) is an RNA-binding
protein that broadly regulates RNA metabolism. Although its nuclear roles
are well-studied, evidence of SFPQ’s cytoplasmic functionality is
emerging. Altered expression and nuclear-to-cytoplasmic redistribution of
SFPQ have been recognised in amyotrophic lateral sclerosis (ALS)
pathology, yet the mechanistic basis of this remains undetermined. We
identified altered SFPQ splicing in ALS, increasing the expression of an
alternative mRNA isoform lacking a nuclear localisation sequence, which we
termed ‘altSFPQ’. We find that altSFPQ mRNA contributes to SFPQ
autoregulation and is highly unstable yet exhibits context-specific
translation with cytoplasm-predominant localisation. Notably, reduced
canonical SFPQ coincides with increased altSFPQ transcript expression in
familial and sporadic ALS models, providing a mechanistic basis for SFPQ
nuclear-to-cytoplasmic redistribution in ALS patients. Finally, we observe
that the altSFPQ protein has reduced phase separation potential and
differential protein binding compared to its canonical counterpart,
providing insight into its mechanistic relevance to physiology and ALS
pathogenesis.