Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.
Dong LiuHannah C WebberFuyun BianYangfan XuManjari PrakashXue FengMing YangHang YangIn-Jee YouLiang LiLiping LiuPingting LiuHaoliang HuangChien-Yi ChangLiang LiuSahil H ShahAnna La TorreDerek S WelsbieYang SunXin DuanJeffrey Louis GoldbergMarcus BraunZdenek LanskyYang HuPublished in: bioRxiv : the preprint server for biology (2024)
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∆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.
Keyphrases
- optic nerve
- amyotrophic lateral sclerosis
- late onset
- spinal cord
- optical coherence tomography
- spinal cord injury
- oxidative stress
- stem cells
- cell death
- diabetic rats
- high glucose
- induced apoptosis
- early onset
- reactive oxygen species
- blood pressure
- endoplasmic reticulum
- drug induced
- cell cycle arrest
- cell proliferation
- single molecule
- pi k akt
- stress induced