An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.
Loading...
Embargo End Date
ICR Authors
Authors
Neeves, J
Petrić Howe, M
Ziff, OJ
Callaghan, B
Jutzi, D
Pal, K
Roumeliotis, TI
Choudhary, J
Isaacs, AM
Rigo, F
Bennett, CF
Ruepp, M-D
Patani, R
Petrić Howe, M
Ziff, OJ
Callaghan, B
Jutzi, D
Pal, K
Roumeliotis, TI
Choudhary, J
Isaacs, AM
Rigo, F
Bennett, CF
Ruepp, M-D
Patani, R
Document Type
Journal Article
Date
2025-08-22
Date Accepted
2025-07-18
Abstract
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 recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined. We identified altered SFPQ splicing in ALS, increasing the expression of an alternative mRNA isoform lacking a nuclear localization 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 localization. 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 patients with ALS. Last, 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.
Citation
Science Advances, 2025, 11 (34), pp. eadt4814 -
Source Title
Science Advances
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
2375-2548
eISSN
2375-2548
Collections
Research Team
Functional Proteomics
Prote & Metabolomics Fac
Prote & Metabolomics Fac