PUBLICATION
Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons
- Authors
- Asakawa, K., Handa, H., Kawakami, K.
- ID
- ZDB-PUB-200225-12
- Date
- 2020
- Source
- Nature communications 11: 1004 (Journal)
- Registered Authors
- Asakawa, Kazuhide, Kawakami, Koichi
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 32081878 Full text @ Nat. Commun.
Citation
Asakawa, K., Handa, H., Kawakami, K. (2020) Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. Nature communications. 11:1004.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping