論文 - 詳細
RRC ID | 60099 |
---|---|
著者 | Asakawa K, Handa H, Kawakami K. |
タイトル | Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. |
ジャーナル | Nat Commun |
Abstract |
Cytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS). Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defect associated with myofiber denervation. In contrast, opTDP-43 forms pathological aggregates in the cytoplasm after longer-term illumination and seeds non-optogenetic TDP-43 aggregation. Furthermore, we find that an ALS-linked mutation in the intrinsically disordered region (IDR) exacerbates the light-dependent opTDP-43 toxicity on locomotor behavior. Together, our results propose that IDR-mediated TDP-43 oligomerization triggers both acute and long-term pathologies of motor neurons, which may be relevant to the pathogenesis and progression of ALS. |
巻・号 | 11(1) |
ページ | 1004 |
公開日 | 2020-2-21 |
DOI | 10.1038/s41467-020-14815-x |
PII | 10.1038/s41467-020-14815-x |
PMID | 32081878 |
PMC | PMC7035286 |
MeSH | Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism* Amyotrophic Lateral Sclerosis / pathology* Animals Animals, Genetically Modified DNA-Binding Proteins / chemistry* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Disease Models, Animal Humans Intrinsically Disordered Proteins / chemistry Intrinsically Disordered Proteins / genetics Intrinsically Disordered Proteins / metabolism Models, Molecular Motor Neurons / metabolism* Motor Neurons / pathology* Mutation Optogenetics Protein Aggregation, Pathological / genetics Protein Aggregation, Pathological / metabolism Protein Multimerization Protein Stability Spinal Cord / metabolism* Spinal Cord / pathology* Up-Regulation Zebrafish |
IF | 11.878 |
引用数 | 1 |
リソース情報 | |
ゼブラフィッシュ | Tg[UAS:mRFP1-TDP-43z] Tg[UAS:mRFP1-CRY2olig] Tg[UAS:opTDP-43z] Tg[mnr2b-hs:EGFP-TDP-43z] Tg[mnr2b-hs:opTDP-43h] Tg[mnr2b-hs:opTDP-43hA315T] |