RRC ID 60099
Author Asakawa K, Handa H, Kawakami K.
Title Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons.
Journal Nat Commun
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.
Volume 11(1)
Pages 1004
Published 2020-2-21
DOI 10.1038/s41467-020-14815-x
PII 10.1038/s41467-020-14815-x
PMID 32081878
PMC PMC7035286
MeSH 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
IF 11.878
Times Cited 1
Resource
Zebrafish