Establishment of chemically oligomerizable TAR DNA-binding protein-43 which mimics amyotrophic lateral sclerosis pathology in mammalian cells
| Autor: | Yoshiaki Yamanaka, Yuichiro Harada, Tamami Miyagi, Kohsuke Kanekura, Masahiko Kuroda |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty TIA1 TAR DNA-Binding Protein 43 medicine.disease_cause Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Sequestosome 1 In vivo mental disorders medicine Humans Amyotrophic lateral sclerosis Nuclear export signal education Molecular Biology Mutation education.field_of_study Chemistry Amyotrophic Lateral Sclerosis nutritional and metabolic diseases Cell Biology medicine.disease nervous system diseases DNA-Binding Proteins Cytosol 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis HeLa Cells |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology. 101(10) |
| ISSN: | 1530-0307 |
| Popis: | One of the pathological hallmarks of amyotrophic lateral sclerosis (ALS) is mislocalized, cytosolic aggregation of TAR DNA-Binding Protein-43 (TDP-43). Not only TDP-43 per se is a causative gene of ALS but also mislocalization and aggregation of TDP-43 seems to be a common pathological change in both sporadic and familial ALS. The mechanism how nuclear TDP-43 transforms into cytosolic aggregates remains elusive, but recent studies using optogenetics have proposed that aberrant liquid-liquid phase separation (LLPS) of TDP-43 links to the aggregation process, leading to cytosolic distribution. Although LLPS plays an important role in the aggregate formation, there are still several technical problems in the optogenetic technique to be solved to progress further in vivo study. Here we report a chemically oligomerizable TDP-43 system. Oligomerization of TDP-43 was achieved by a small compound AP20187, and oligomerized TDP-43 underwent aggregate formation, followed by cytosolic mislocalization and induction of cell toxicity. The mislocalized TDP-43 co-aggregated with wt-TDP-43, Fused-in-sarcoma (FUS), TIA1 and sequestosome 1 (SQSTM1)/p62, mimicking ALS pathology. The chemically oligomerizable TDP-43 also revealed the roles of the N-terminal domain, RNA-recognition motif, nuclear export signal and low complexity domain in the aggregate formation and mislocalization of TDP-43. The aggregate-prone properties of TDP-43 were enhanced by a familial ALS-causative mutation. In conclusion, the chemically oligomerizable TDP-43 system could be useful to study the mechanisms underlying the droplet-aggregation phase transition and cytosolic mislocalization of TDP-43 in ALS and further study in vivo. |
| Databáze: | OpenAIRE |
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