浅川 和秀 / Kazuhide Asakawa:1 川上 浩一 / Koichi Kawakami:1,2
Spinal motor neurons are primary targets of neurodegeneration in amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43, Tardbp) characterize these neurons undergoing degeneration, but how TDP-43 contributes to neuronal dysfunction and degeneration has not been fully understood. To understand early pathological changes of spinal motor neurons caused by TDP-43, we employ the zebrafish caudal primary motor neuron (CaP), a whole cell of which is optically and genetically accessible to measurement and manipulation. We find that both knockout and overexpression of TDP-43 reduce total axon arbor length approximately by 20%. Intriguingly, in the overexpression condition, the neuromuscular synapse formation and neuronal excitability are also diminished in the absence of accumulation of cytoplasmic TDP-43 aggregates. We further discover that targeted activation of PI3Kα/the mammalian target of rapamycin (mTOR) pathway rescues the defects in axon outgrowth, synapse formation and neuronal excitability. We also find that treatment of rapamycin, an inihibitor of mTOR, diminishes axon outgrowth of CaPs in the wild type fish, suggesting that PI3Kα/mTOR pathway is an intrinsic promoter of axon outgrowth in the spinal motor neuron. Based on these observations, we propose that neuronal atrophy derived from aberrant TDP-43 proteostasis is one of the earliest pathological changes caused by TDP-43 in the spinal motor neuron, and that activation of the PI3Kα/mTOR pathway might serve as a potential strategy to maintain or restore functional motor units in ALS.