Localization of Potential Energy in Hydrogen Bonds of the ATXN2 Gene

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 933 - 933

Published: Jan. 23, 2025

It is known that a number of neurodegenerative diseases, also called diseases waiting, are associated with the expansion polyQ tract in first exon ATXN2 gene. In expanded tract, probability occurrence non-canonical configurations (hairpins, G-quadruplexes, etc.) significantly higher than normal one. Obviously, for their formation, open states (OSs) necessary. Calculations were made these processes using angular mechanical model DNA. has been established large OS zones genesis DNA segment depends not only on “strength” nucleotide sequence but factors determining dynamics DNA; localization energy molecule and potential interaction between pairs nitrogenous bases depend environmental parameters. The hydrogen bonds does remain constant, oscillatory movements lead to its redistribution localization. this case, OSs effectively dissipate oscillations. Thus, mathematical modeling makes it possible calculate energy, which necessary predict places origin, taking into account oscillations molecule.

Language: Английский

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Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality

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

Published: Feb. 13, 2025

Language: Английский

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The LSmAD Domain of Ataxin-2 Modulates the Structure and RNA Binding of Its Preceding LSm Domain

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

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ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation

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

Published: March 11, 2025

Abstract The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly nuclear, more abundant, essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. study, we utilized two approaches clarify the roles of ATXN2L. First, identified interactors through co-immunoprecipitation both wild-type ATXN2L-null murine fibroblasts. Second, assessed proteome profile effects using mass spectrometry these cells. Additionally, examined accumulation ATXN2L SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, HNRNPDL, exhibit a stronger association compared established like ATXN2, PABPC1, LSM12, G3BP2. interacted components actin complex, such as SYNE2, LMOD1, ACTA2, FYB, GOLGA3. noted oxidative increased HNRNPK but decreased SYNE2 association, which likely reflects relocalization SG. Proteome profiling revealed NUFIP2 are depleted Furthermore, homodimers SYNE1 accumulate during aggregation process KIN 14-month-old spinal cord tissues. functions its therefore critical granule trafficking surveillance, particularly maintenance differentiated neurons.

Language: Английский

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ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 209, P. 106903 - 106903

Published: April 11, 2025

Language: Английский

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Targets and Gene Therapy of ALS (Part 1)

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4063 - 4063

Published: April 25, 2025

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms ALS are recorded only in 10% cases. However, over past decade, studies genetics have substantially contributed to our understanding molecular mechanisms underlying ALS. The identification key mutations such as SOD1, C9orf72, FUS, and TARDBP has led development targeted therapy that gradually being introduced into clinical trials, opening up broad range opportunities for correcting these mutations. In this review, we aimed present an extensive overview currently known neuron degeneration associated with genes also gene methods inhibiting expression their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA miRNA), gene-editing (CRISPR/Cas9) particular interest. Each shown its efficacy animal models when targeting genes, whereas some them proven be efficient human trials.

Language: Английский

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Characterization of the association and sequestration of RNA-binding proteins by single-stranded DNA chimera

Acta Biochimica et Biophysica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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The Potential of Mesenchymal Stem Cells in Treating Spinocerebellar Ataxia: Advances and Future Directions

Biomedicines, Journal Year: 2024, Volume and Issue: 12(11), P. 2507 - 2507

Published: Nov. 1, 2024

Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused cerebellar dysfunction. The absence of treatments approved the U.S. Food Drug Administration for SCA has driven investigation alternative therapeutic strategies, including stem cell therapy. Mesenchymal cells (MSCs), known their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, modulate brain inflammation. Recent findings from preclinical clinical studies are also reviewed, emphasizing promise MSC therapy addressing unmet needs patients. Furthermore, ongoing trials future directions proposed to address limitations current approaches.

Language: Английский

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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

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

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