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.

Department of Cell Biology and Human Anatomy University of California Davis CA USA

Department of Electrical Engineering Stanford University Stanford CA USA

Department of Ophthalmology University of California San Francisco San Francisco CA USA

Eye Institute and Department of Ophthalmology Eye and ENT Hospital Fudan University; NHC Key Laboratory of Myopia Key Laboratory of Myopia Chinese Academy of Medical Sciences; Shanghai Research Center of Ophthalmology and Optometry Shanghai P R China

Institute of Biotechnology Czech Academy of Sciences BIOCEV Vestec Prague West Czechia

Spencer Center for Vision Research Department of Ophthalmology Byers Eye Institute at Stanford University School of Medicine Palo Alto CA USA

Viterbi Family Department of Ophthalmology University of California San Diego San Diego CA USA

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bioRxiv. 2024 Apr 03:2024.04.02.587832. doi: 10.1101/2024.04.02.587832. PubMed

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