ALS-Linked Mutant SOD1 Associates with TIA-1 and Alters Stress Granule Dynamics
- PDF / 1,522,367 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 66 Downloads / 144 Views
ORIGINAL PAPER
ALS‑Linked Mutant SOD1 Associates with TIA‑1 and Alters Stress Granule Dynamics Do‑Yeon Lee1 · Gye Sun Jeon1,2 · Jung‑Joon Sung1,3 Received: 30 December 2019 / Revised: 18 September 2020 / Accepted: 21 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Amyotrophic lateral sclerosis (ALS) is a degenerative disorder caused by motor neuron loss. T-cell intracellular antigen-1 (TIA-1), a cytotoxic T lymphocyte granule-associated RNA binding protein, is a key component of stress granules. However, it remains uncertain whether ALS-causing superoxide dismutase-1 (SOD1) toxicity alters the dynamics of stress granules. Thus, through mouse and cell line models, and human cells and tissues, we showed the subcellular location of TIA-1 and its recruitment by stress granules following mutant SOD1-related stimuli. An overexpression of MTSOD1 resulted in increased TIA-1-positive cytoplasmic inclusions in the spinal cord tissue of SOD1G93A transgenic mouse and the SOD1G86S familial ALS patient. Moreover, we demonstrated the stages of ALS-like disease-dependent increase in TIA-1 in the spinal cord of transgenic mice. A similar increase of TIA-1 was found in the spinal cord of the SOD1G86S patient and induced pluripotent stem cell-derived neural stem cells from the SOD1G17S patient. By using immunoprecipitation assays in wild type (WT) human SOD1 (hSOD1) or mutant (MT) hSOD1-transfected motor neuronal cell lines and SOD1G93A transgenic mouse model, we observed that MTSOD1 interacts with TIA-1. In WT or MT hSOD1-transfected HEK293 and NSC-34 cells, the formation of TIA-1-positive stress granules was delayed in MTSOD1 by sodium arsenite treatment. These findings suggest that MTSOD1 could affect the dynamics of stress granules through the abnormal MTSOD1-TIA-1 interaction. Consequently, the resulting pathological TIA-1 may be involved in RNA metabolism found in ALS. Keywords SOD1 · Stress granules · TIA-1 · Amyotrophic lateral sclerosis · RNA binding proteins
Introduction Amyotrophic lateral sclerosis (ALS) is a known fatal neurodegenerative disorder that cause the death of motor neurons in the brain and the spinal cord [1–3]. The pathogenesis of Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11064-020-03137-5) contains supplementary material, which is available to authorized users. * Gye Sun Jeon [email protected] * Jung‑Joon Sung [email protected] 1
Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
2
Biomedical Research Institute, Seoul National University Hospital College of Medicine, Seoul, South Korea
3
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea
ALS is largely unknown, but proposed pathological features suggest that it is the consequence of abnormal protein aggregation, mitochondrial and oxidative stress, inflammation, glutamate toxicity, RNA dysfunction, calcium-me
Data Loading...
