Multiomics approach identifies SERPINB1 as candidate progression biomarker for Spinocerebellar Ataxia type 2 DOI
Luis E. Almaguer-Mederos,

Jana Key,

Nihat Şen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Abstract Background Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. Objectives The aim this study was to define novel biomarker candidates Methods Using cerebellar cervicothoracic spinal cord RNA from Atxn2 -CAG100-KnockIn wildtype mice, multi-omics conducted, followed by validation mice humans. Global transcriptome studies were conducted using Clariom D microarray. Extracted proteins analyzed LC-MS/MS global proteomics, Immobilized Metal Affinity Chromatography phosphoproteomics. Validation assessed expression RT-qPCR, abundance quantitative immunoblots ELISA. Patients with SCA2 diagnosed following standard procedures, age at onset, SARA score, INAS count, duration used clinical severity markers. Results Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a -transcript, SERPINB1A-protein -phosphopeptides consistently downregulated terminal stage 14-month-old KnockIn mice. Expression cerebellum 10 weeks (pre-manifest), 6-month-old (early ataxic), (late ataxic stage) confirmed progressive decrease mRNA level. SERPINB1 plasma levels significantly lower patients, displayed significant association CAG repeat length expanded ATXN2 alleles also showing trend towards significance score. Conclusions identified promising specificity pathomechanisms.

Language: Английский

Multiomics approach identifies SERPINB1 as candidate progression biomarker for Spinocerebellar Ataxia type 2 DOI
Luis E. Almaguer-Mederos,

Jana Key,

Nihat Şen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Abstract Background Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. Objectives The aim this study was to define novel biomarker candidates Methods Using cerebellar cervicothoracic spinal cord RNA from Atxn2 -CAG100-KnockIn wildtype mice, multi-omics conducted, followed by validation mice humans. Global transcriptome studies were conducted using Clariom D microarray. Extracted proteins analyzed LC-MS/MS global proteomics, Immobilized Metal Affinity Chromatography phosphoproteomics. Validation assessed expression RT-qPCR, abundance quantitative immunoblots ELISA. Patients with SCA2 diagnosed following standard procedures, age at onset, SARA score, INAS count, duration used clinical severity markers. Results Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a -transcript, SERPINB1A-protein -phosphopeptides consistently downregulated terminal stage 14-month-old KnockIn mice. Expression cerebellum 10 weeks (pre-manifest), 6-month-old (early ataxic), (late ataxic stage) confirmed progressive decrease mRNA level. SERPINB1 plasma levels significantly lower patients, displayed significant association CAG repeat length expanded ATXN2 alleles also showing trend towards significance score. Conclusions identified promising specificity pathomechanisms.

Language: Английский

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