Post-symptomatic administration of hMSCs exerts therapeutic effects in SCA2 mice DOI Creative Commons
Sehwan Kim, Chanchal Sharma,

Jungwan Hong

et al.

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 9, 2024

Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion its coding gene, Atxn-2, cause neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, exact mechanisms underlying their therapeutic effects interaction with host tissue to stimulate neurotrophin expression remain unclear specifically context SCA2.

Language: Английский

PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6 DOI Creative Commons
Jianyang Wang, Yajun Liu,

Xiangle Zhang

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(7), P. 107413 - 107413

Published: May 27, 2024

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, molecular mechanism underlying how Atx2 contributes to proteinopathies remains elusive. Here, we investigated influence on assembly and functionality cellular processing bodies (P-bodies) by using biochemical fluorescence imaging approaches. We have revealed polyQ-expanded (PQE) sequesters DEAD-box RNA helicase (DDX6), an essential component P-bodies, into aggregates or puncta via some sequences. The N-terminal like-Sm (LSm) domain (residues 82-184) C-terminal DDX6 are responsible for interaction specific sequestration. Moreover, sequestration aggravate pre-mRNA mis-splicing, interfere with releasing endoribonuclease MARF1 promotes mRNA decay translational repression. Rescuing level can recover P-bodies preventing targeted from degradation. This study provides line evidence P-body components impairment homeostasis dysregulating metabolism, which disease pathologies potential therapeutic target.

Language: Английский

Citations

8
Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality DOI Creative Commons

Xiangle Zhang,

Hongwei Yue, Yajun Liu

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112025 - 112025

Published: Feb. 13, 2025

Language: Английский

Citations

0
Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2 DOI
Sehwan Kim, Jun‐Woo Park,

Hyemi Eo

et al.

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

0
The LSmAD Domain of Ataxin-2 Modulates the Structure and RNA Binding of Its Preceding LSm Domain DOI Creative Commons
Shengping Zhang, Yun‐Long Zhang, Ting Chen

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 383 - 383

Published: March 6, 2025

Ataxin-2 (Atx2), an RNA-binding protein, plays a pivotal role in the regulation of RNA, intracellular metabolism, and translation within cellular environment. Although both Sm-like (LSm) LSm-associated (LSmAD) domains are considered to associated with RNA binding, there is still lack experimental evidence supporting their functions. To address this, we designed constructed several recombinants containing domain (RBD) Atx2. By employing biophysical biochemical techniques, such as EMSA SHAPE chemical detection, identified that LSm responsible for whereas LSmAD alone does not bind RNA. NMR small-angle X-ray scattering (SAXS) analyses have revealed exhibits limited structural integrity poor folding capability. The data confirmed LSm-LSmAD cannot, suggesting may serve auxiliary domain. probing further demonstrates binds AU-rich, GU-rich, or CU-rich sequence, but CA-rich sequence. These findings indicate Atx2 can interact U-rich sequences 3'-UTR, implicating its poly(A) tailing mRNA degradation.

Language: Английский

Citations

0
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

Citations

0
Spinal cord phosphoproteome of a SCA2/ALS13 mouse model reveals alteration of ATXN2-N-term SH3-actin interactome and of autophagy via WNK1-MYO6-OPTN-SQSTM1 DOI Open Access
Luis E. Almaguer-Mederos, Arvind Reddy Kandi,

Nesli-Ece Şen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Abstract Toxic polyglutamine (polyQ) expansions in ATXN2 trigger neurodegenerative processes, causing Spinocerebellar Ataxia type 2 (SCA2), and enhancing TDP-43-dependent pathology Amyotrophic Lateral Sclerosis (ALS) / Fronto-Temporal Dementia (FTD). Primary disease events can be compensated transiently, delaying manifestation. To define potential therapy targets, we documented how cells modify their phospho-signals the interactome changes, using preferentially affected nervous tissues from end-stage Atxn2 -CAG100-KnockIn mice. The spinal cord phosphorylome revealed massive hyperphosphorylations flanking polyQ expansion for SQSTM1, moderate also ALS proteins OPTN, UBQLN2, TNIP1 TBK1-targeted TAX1BP1, versus strong hypophosphorylations of WNK1, SPARCL1 PSMD9. Significant enrichments SH3-containing proteins, autophagy endocytosis factors, actin modulators could explained by N-terminal, polyQ-adjacent, proline-rich motifs ATXN2. Coimmunoprecipitation profiling cerebellum known associations with RNA-binding like PABPC1 TDP-43 its modifier PPIA to decrease upon expansion, contrasting increased binding SH3-proteins, MYO6, RPL21 DLG4. Validation protein mRNA levels mouse cord, embryonic fibroblasts or patient after bafilomycin arsenite treatment, observed polyQ-dependent OPTN deficiency SQSTM1 induction impairment. Overall, this combined phosphoproteome study efficiently key pathways molecular events.

Language: Английский

Citations

0
Post-symptomatic administration of hMSCs exerts therapeutic effects in SCA2 mice DOI Creative Commons
Sehwan Kim, Chanchal Sharma,

Jungwan Hong

et al.

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 9, 2024

Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion its coding gene, Atxn-2, cause neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, exact mechanisms underlying their therapeutic effects interaction with host tissue to stimulate neurotrophin expression remain unclear specifically context SCA2.

Language: Английский

Citations

0