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
Zebrafish hspGFFDMC130A, UAS:GFP, UAS:GCaMP7a, SAIGFF213A