Membrane-associated shortened Trk receptors promote neuroprotection and robust axon regeneration without ligands

Nishijima, E.; Honda, S.; Kitamura, Y.; Namekata, K.; Kimura, A.; Guo, X.; Azuchi, Y.; Harada, C.; Murakami, A.; Matsuda, A.; Nakano, T.; Parada, L.; Harada, T.

doi:10.1101/2022.05.11.491487

bioRxiv · 10.1101/2022.05.11.491487

Membrane-associated shortened Trk receptors promote neuroprotection and robust axon regeneration without ligands

Nishijima, E.·Honda, S.·Kitamura, Y.·Namekata, K.·Kimura, A.·Guo, X.·Azuchi, Y.·Harada, C.·Murakami, A.·Matsuda, A.·Nakano, T.·Parada, L.·Harada, T.

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Abstract

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, limited availability of both ligands and receptors permits only transient activation. In this study, we conquered this problem by inventing a new system that forces membrane localization of the intracellular domain of neurotrophin receptor TrkB, which results in constitutive activation without ligands. Our new system overcomes the small size limitation of the genome packaging in adeno-associated virus and allows high expression of the transgene. Single gene therapy using the modified form of TrkB enhances neuroprotection in mose models of glaucoma, and stimulates robust axon regeneration after optic nerve injury. Our system may be also applicable to other trophic factor signaling and lead to a significant advance in the field of gene therapy for neurodegenerative disorders.

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Nishijima, E., Honda, S., Kitamura, Y., Namekata, K., Kimura, A., Guo, X., Azuchi, Y., Harada, C., Murakami, A., Matsuda, A., Nakano, T., Parada, L., Harada, T.. 2022-05-11. Membrane-associated shortened Trk receptors promote neuroprotection and robust axon regeneration without ligands. https://doi.org/10.1101/2022.05.11.491487

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