|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.
|Source:||Nature communications 11: 1004 (Journal)|
|Registered Authors:||Asakawa, Kazuhide, Kawakami, Koichi|
|PubMed:||32081878 Full text @ Nat. Commun.|
Asakawa, K., Handa, H., Kawakami, K. (2020) Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. Nature communications. 11:1004.
ABSTRACTCytoplasmic 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.