| RRC ID |
77821
|
| Author |
Asakawa K, Handa H, Kawakami K.
|
| Title |
Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish.
|
| Journal |
Dev Growth Differ
|
| 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 remains 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.
|
| Volume |
65(8)
|
| Pages |
446-452
|
| Published |
2023-10-1
|
| DOI |
10.1111/dgd.12879
|
| PMID |
37452624
|
| MeSH |
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
|
| IF |
1.723
|
| Resource |
| Zebrafish |
hspGFFDMC130A, UAS:GFP, UAS:GCaMP7a, SAIGFF213A |
