PUBLICATION
Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish
- Authors
- Asakawa, K., Handa, H., Kawakami, K.
- ID
- ZDB-PUB-230716-42
- Date
- 2023
- Source
- Development, growth & differentiation 65(8): 446-452 (Journal)
- Registered Authors
- Asakawa, Kazuhide, Kawakami, Koichi
- Keywords
- ALS, Spinal motor neuron, TDP-43, calcium imaging, locomotion
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- Calcium/metabolism
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Humans
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Proteostasis
- Spinal Cord
- Zebrafish/metabolism
- PubMed
- 37452624 Full text @ Dev. Growth Diff.
Citation
Asakawa, K., Handa, H., Kawakami, K. (2023) Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish. Development, growth & differentiation. 65(8):446-452.
Abstract
Spinal motor neurons (SMNs) are the primary target of degeneration in amyotrophic lateral sclerosis (ALS). Degenerating motor neurons accumulate cytoplasmic TAR DNA-binding protein 43 (TDP-43) aggregates in most ALS cases. This SMN pathology can occur without mutation in the coding sequence of the TDP-43-encoding gene, TARDBP. Whether and how wild-type TDP-43 drives pathological changes in SMNs in vivo remain largely unexplored. In this study, we develop a two-photon calcium imaging setup in which tactile-evoked neural responses of motor neurons in the brainstem and spinal cord can be monitored using the calcium indicator GCaMP. We devise a piezo-assisted tactile stimulator that reproducibly evokes a brainstem descending neuron upon tactile stimulation of the head. A direct comparison between caudal primary motor neurons (CaPs) with or without TDP-43 overexpression in contiguous spinal segments demonstrates that CaPs overexpressing TDP-43 display attenuated Ca2+ transients during fictive escape locomotion evoked by the tactile stimulation. These results show that excessive amounts of TDP-43 protein reduce the neuronal excitability of SMNs and potentially contribute to asymptomatic pathological lesions of SMNs and movement disorders in patients with ALS. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping