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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 …