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PreprintCited by 34Glaucoma and retinal disordersAmyotrophic Lateral Sclerosis ResearchHereditary Neurological Disorders

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Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

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Liu, Dong, Webber, Hannah C., Bian, Fuyun, Xu, Yangfan, Prakash, Manjari, Feng, Xue, Yang, Ming, Yang, Hang, You, In-Jee, Li, Liang, Liu, Liping, Liu, Pingting, Huang, Haoliang, Chang, Chien-Yi, Liu, Liang, Shah, Sahil H, Torre, Anna La, Welsbie, Derek S., Sun, Yang, Duan, Xin, Goldberg, Jeffrey Louis, Braun, Marcus, Lansky, Zdenek, Hu, Yang·2024·Nature Communications
DOI 10.1101/2024.04.02.587832PMC PMC11842812

Preprint — published as 10.1038/s41467-025-57135-8 · Paper page

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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 (OPTNΔC) 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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Metadata

Authors
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., Liu, L., Shah, S. H., Torre, A. L., Welsbie, D. S., Sun, Y., Duan, X., Goldberg, J. L., Braun, M., Lansky, Z., & Hu, Y.
Affiliations
  • Stanford University (US)
  • Shanghai Medical College of Fudan University (CN)
  • Czech Academy of Sciences (CZ)
  • University of California, Davis (US)
  • University of California San Diego (US)
  • University of California, San Francisco (US)
  • Stanford Medicine (US)
Corresponding author
Hu, Yang
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-04-03
Volume
16
Issue
1
Pages
1789-1789
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.04.02.587832
PMC
PMC11842812
OpenAlex
W4407796432
Cited by
34
References
1
Citations by year
2026: 18 · 2025: 14 · 2024: 2
FWCI
27.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Durham Research Online (Durham University) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services (EY034353, EY032518, EY024932, 1F32EY029567, EY026877, EY023295)
  • Glaucoma Research Foundation
  • Research to Prevent Blindness (EY026877, CX001298)
  • Children's Health Research Institute
  • National Natural Science Foundation of China
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LM2023050, CZ.02.1.01/0.0/0.0/18_046/0015974, RVO:86652036, CZ.02.1.01, 86652036, LM2023042)
  • Grantová Agentura České Republiky (CZ.02.1.01/0.0, RVO 86652036, 86652036, LM2023042, GA23-07703S, CZ.02.1.01, LM2023050, GX19-27477X, GA22-11753S)
  • Science and Technology Commission of Shanghai Municipality
  • National Institutes of Health (86652036, 1s10od012276-01, 1s10od025091-01, CX001298, 1s10od030452-01, 5f32ey029567-02, EY 026877)
  • European Regional Development Fund (02.1.01/0.0/0.0, CZ.02.1.01/0.0/0.0/18_046/0015974, CZ.02, CZ.02.1.01, CZ.02.1.01/0.0/0.0, 86652036)
  • National Eye Institute (R01EY032159, R01EY023295, EY026877, 1F32EY029567, EY024932, EY023295, EY034353, CX001298, EY032518, F32 EY029567, R01EY032518, R01EY025295, R01EY024932, R01EY034353, P30EY026877)
  • National Center for Research Resources (1S10OD01227601, 1S10OD030452-01)
  • HORIZON EUROPE European Research Council (101071583)
Topics
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
optineurin, microtubule stabilization, neurodegeneration, retinal ganglion cells, optic nerve regeneration, amyotrophic lateral sclerosis, normal-tension glaucoma, ocular hypertension, axon protection, animal models

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