Study Of The Genetic Correlation And Pathological Mechanism Between Variants In SFPQ Gene And Amyotrophic Lateral Sclerosis

Background: Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease with a high degree of clinical heterogeneity,as well as a lack of early diagnostic signs and effective medicines.An increasing number of recent literatures has demonstrated that the important implications of SFPQ in neurodegenerative diseases such as amyotrophic lateral sclerosis(ALS)frontotemporal lobar degeneration(FTLD),and Alzheimer’s disease(AD).The cytoplasmic mislocalization and aggregation of RBPs have been emerging as new hallmarks of neurodegenerative diseases.Hitherto,the research about the association between the ALS and SFPQ are limited to functional analysis and there is no systematic analysis of SFPQ variants has been conducted in a large cohort.Objectives: In the present study,we screened rare,pathogenic SFPQ variants among a cohort of patients with ALS from mainland China and performed burden analysis to investigate the potential contribution of SFPQ variants to ALS.Meanwhile,we preliminarily explore the pathogenesis of ALS caused by SFPQ variants in mainland China to provide a new research direction for the clinical diagnosis and treatment targets of ALS.Methods: In this study,we screened rare,pathogenic SFPQ variants among a cohort of 1054 patients with ALS from mainland China and performed burden analysis using data from the gnom AD database v2.1with 6708 individuals without neurological disease of East Asian population.Meanwhile,we did the same test by using the date from ALSdb cohort including 3317 ALS patients and the gnom AD database v2.1 with104068 individuals without neurological disease.Subsequently,we did much functional research,such as Western blotting,immunofluorescence,immunoprecipitation to explore the pathogenesis of ALS caused by SFPQ variants.Results: A total of 4 rare,pathogenic variants in SFPQ(p.A390G、p.A419V、p.R583H、p.A672V)were identified in 8 unrelated patients from 1054 ALS patients.Variant p.A390 G was identified in 5 probands.gene burden testing was significant for SFPQ variants as a risk factor for ALS(chi-square test,p=0.004).In addition,the validation results also found that SFPQ variants were also significantly enriched in ALS patients.Meanwhile,functional examination revealed that ALS-associated SFPQ variants(p.R583H、p.A672V)affect stress granule(SGs)assembly.The variants(p.A419 V,p.R583 H,p.A672V)enhanced the binding of KIF5 A and variants p.A419 V enhanced the binding of m RNA(bclw、laminb2)which encode proteins that promote axon survival.Conclusion: Our results suggested that pathogenic SFPQ variants may be a risk factor for ALS and may cause a predisposition to ALS through affecting the SGs assembly and the axon survival.