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

被引:62
作者
Asakawa, Kazuhide [1 ,2 ,3 ]
Handa, Hiroshi [1 ]
Kawakami, Koichi [2 ,3 ]
机构
[1] Tokyo Med Univ, Dept Biol Chem, Shinjuku Ku, Tokyo 1608402, Japan
[2] Natl Inst Genet, Div Mol & Dev Biol, 1111 Yata, Mishima, Shizuoka 4118540, Japan
[3] Grad Univ Adv Studies SOKENDAI, Dept Genet, 1111 Yata, Mishima, Shizuoka 4118540, Japan
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; RNA TARGETS; MOUSE MODEL; AGGREGATION; DISEASE; MUTATIONS; ZEBRAFISH; MOTONEURONS; INCLUSIONS;
D O I
10.1038/s41467-020-14815-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:16
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