Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Liu, D.; Webber, H. C.; Bian, F.; Xu, Y.; Prakash, M.; Feng, X.; Yang, M.; Yang, H.; You, I.-J.; Li, L.; Liu, L.; Liu, P.; Huang, H.; Chang, C.-Y.; Shah, S. H.; La Torre, A.; Welsbie, D. S.; Sun, Y.; Duan, X.; Goldberg, J. L.; Braun, M.; Lansky, Z.; Hu, Y.

doi:10.1101/2024.04.02.587832

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bioRxiv · 10.1101/2024.04.02.587832

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

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Abstract

Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN{Delta}C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C- terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.

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Liu, D., Webber, H. C., Bian, F., Xu, Y., Prakash, M., Feng, X., Yang, M., Yang, H., You, I.-J., Li, L., Liu, L., Liu, P., Huang, H., Chang, C.-Y., Shah, S. H., La Torre, A., Welsbie, D. S., Sun, Y., Duan, X., Goldberg, J. L., Braun, M., Lansky, Z., Hu, Y.. 2024-04-03. Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration. https://doi.org/10.1101/2024.04.02.587832

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