Journal Article

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

Asakawa, Kazuhide, Handa, Hiroshi, Kawakami, Koichi

2020

Overview

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. Optogenetic approaches for inducing TDP-43 aggregation have been described previously in cellular models. Here the authors develop an approach to optogenetically induce TDP-43 aggregation in vivo using zebrafish to model ALS pathologies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/35 / 631/378/1689/1285 / 631/378/1689/364 / 64/116 / 82/1 / Agglomeration / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animals / Animals, Genetically Modified / Biocompatibility / Cytoplasm / Danio rerio / Denervation / Disease Models, Animal / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Humanities and Social Sciences / Humans / Illumination / Intrinsically Disordered Proteins - chemistry / Intrinsically Disordered Proteins - genetics / Intrinsically Disordered Proteins - metabolism / Light / Models, Molecular / Motor neurons / Motor Neurons - metabolism / Motor Neurons - pathology / multidisciplinary / Mutation / Neuromuscular system / Neurons / Oligomerization / Optogenetics / Pathogenesis / Protein Aggregation, Pathological - genetics / Protein Aggregation, Pathological - metabolism / Protein Multimerization / Protein Stability / Science / Science (multidisciplinary) / Seeds / Spinal Cord - metabolism / Spinal Cord - pathology / Toxicity / Up-Regulation / Zebrafish