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<p>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 find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. 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. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.</p>

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Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月20日

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

摘要

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 find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. 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. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.