Key, Jana;
Almaguer-Mederos, Luis-Enrique;
Kandi, Arvind Reddy;
Sen, Nesli-Ece;
Gispert, Suzana;
Köpf, Gabriele;
Meierhofer, David;
(2025)
ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation.
Neurobiology of Disease
, 209
, Article 106903. 10.1016/j.nbd.2025.106903.
Preview |
Text
2025_ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion.pdf - Published Version Download (3MB) | Preview |
Abstract
The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the 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, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.
| Type: | Article |
|---|---|
| Title: | ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.nbd.2025.106903 |
| Publisher version: | https://doi.org/10.1016/j.nbd.2025.106903 |
| Language: | English |
| Additional information: | © 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/bync/4.0/). |
| Keywords: | Interactome profiling, stress granules, Spinocerebellar Ataxia, actin cytoskeleton, proteome profiling, RNA-binding proteins, ribonucleoprotein complexes |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10215976 |
Archive Staff Only
 |
View Item |
