浅川 和秀 / Kazuhide Asakawa:1 川上 浩一 / Koichi Kawakami:1,2
activation alleviates TDP-43-induced axonopathy in the spinal motor neuron in zebrafish
(1:国立遺伝研個体遺伝初期発生 / National Institute of Genetics, Mishima, Japan 2:総研大院遺伝学 / Molecular and Developmental Biology, NIG, Mishima )
TAR DNA-binding protein 43 (TDP-43, TARDBP) is an evolutionarily conserved heterogenous nuclear ribonucleoprotein (hnRNP),
and is a major component of the cytoplasmic inclusions that are pathological hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
Molecular and cellular bases of TDP-43 toxicity that lead to neuronal dysfunction and degeneration, however, have not been fully understood.
In the present study, we developed a system to monitor whole cell morphology, neuromuscular synapse formation,
and neuronal excitability of an identified single spinal motor neuron by taking advantage of the genetic and optical accessibility in zebrafish.
We showed that the perturbation of TDP-43 protein homeostasis by targeted overexpression of the wild-type TDP-43 in the genetically identified spinal motor neuron
(CaP primary motor neuron, hereafter CaP) caused reduced axonal outgrowth and arborization without accumulation of cytoplasmic TDP-43 aggregates. Further,
in vivo two-photon calcium imaging revealed that the perturbed CaP displayed attenuated calcium transients in both the cell body and axon terminals during fictive swimming,
indicating a reduced excitability. Consistently, pan-neuronal induction of TDP-43 resulted in an impaired locomotor activity. By using this TDP-43-induced axonopathy model,
we demonstrated that the targeted activation of PI3 kinase in CaP rescued the TDP-43-induced defects in axonal outgrowth, neuromuscular synapse formation and neuronal excitability.
Thus, our results suggest that perturbation of TDP-43 protein homeostasis can cause neuronal dysfunction in the absence of its cytoplasmic aggregates,
and modulation of PI3 kinase pathway could be a potential therapeutic strategy for ALS and other TDP-43 proteinopathies.