A novel function of optineurin in axonal mitochondria transport for axon integrity and regeneration

Abstract

Purpose : Optineurin (OPTN) mutations cause normal tension glaucoma (NTG) and ALS in human patients, indicating a critical role of OPTN in CNS axon integrity. Although its role as autophagy receptor in mitophagy has been the focus for pathogenesis studies, how OPTN dysfunction leads to neurodegeneration is still not clear. Here we aim to elucidate the molecular mechanism of OPTN-associated neurodegeneration.

Methods : OPTN-C-terminus floxed mouse line, Vglut2-Cre mouse line, and AAV2-mSncg-Cre were used to generate NTG-like and ALS-like mouse neurodegeneration models caused by OPTN C-terminus truncation (OPTNΔC). We used optical coherence tomography, pattern electroretinography, optokinetic response, and various locomotion assays, and histology quantification to determine neurodegeneration. Advanced in vitro biochemistry assays and in vivo imaging assays were employed to determine the novel binding partners of OPTN and their crucial activities in the pathogenesis of CNS neurodegeneration.

Results : OPTNΔC induces progressive retinal ganglion cell (RGC) and optic nerve (ON) degeneration through impeding ON mitochondria distribution. Surprisingly, we found that OPTN binds to microtubule in a C-terminus dependent manner, by which OPTN tethers the mitochondria transport complex TRAK1/KIF5B onto microtubules for adequate mitochondria axonal delivery. Consistently, overexpressing TRAK1/KIF5B in OPTNΔC RGCs preserves RGC/ON morphology and visual functions through increasing mitochondria distribution in ONs. More importantly, we found that ocular hypertension decreases mitochondria transportation in ONs as well, and overexpressing OPTN/TRAK1/KIF5B significantly protects glaucomatous RGCs/ONs and visual functions. Finally, we demonstrate striking ON regeneration phenotype induced by OPTN/TRAK1/KIF5B.

Conclusions : This study reveals a previously unknown function of OPTN in tethering the mitochondria transport machinery onto microtubules and facilitating axonal mitochondria delivery, loss of which is likely the molecular mechanism of OPTN dysfunction-induced neurodegeneration. We established NTG/ALS-like animal models and proposed a promising therapeutic strategy by boosting OPTN/TRAK1/KIF5B-mediated axonal mitochondria delivery for neuroprotection and axon regeneration.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.