ZFIN ID: ZDB-PUB-200225-12
Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons
Asakawa, K., Handa, H., Kawakami, K.
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.
FIGURES
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.
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