Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons

Sep 2, 2025Acta neuropathologica communications

Lack of Optineurin Affects Tau Protein Balance and Clusterin Levels in Human Nerve Cells

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Abstract

A significant negative correlation was found between and specific (pTau) epitopes in neurons.

OPTN protein levels decreased in brain tissues of individuals with Alzheimer's disease.
Loss of OPTN in induced neurons increased specific forms of pTau without significantly affecting autophagy or mitochondrial respiration.
Mitochondrial proteins, including OXCT1, were found to be enriched in the OPTN interactome of induced neurons.
Intracellular , an Alzheimer's disease risk gene, was significantly upregulated in OPTN knockout induced neurons.
The findings suggest that OPTN may have modest roles in neuronal processes and potential effects on Alzheimer's disease pathogenesis.

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(OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking. AD is characterized by the accumulation of extracellular amyloid-β plaques and intracellular (pTau) tangles, with dysfunction in the autophagy-lysosomal pathway exacerbating tau pathology and impairing proteostasis. To investigate the role of OPTN in neuronal proteostasis and AD, we utilized induced pluripotent stem cell-derived neuron (iN) and astrocyte (iA) models. Analyses revealed a significant negative correlation between OPTN and specific pTau epitopes in neurons, as well as a decrease in OPTN protein abundance in brain tissues of individuals with AD. Given these findings, we generated OPTN knockout (KO), heterozygous, and wildtype iNs and iAs using CRISPR/Cas9 editing of iPSCs in two genetic backgrounds. Loss of OPTN in iNs increased specific pTau proteoforms without substantially affecting autophagy processes or mitochondrial respiration. Despite no clear effect on mitochondrial function, several mitochondrial proteins, including OXCT1, were enriched in an unbiased analysis of the OPTN interactome in iNs, as well as proteins involved in intracellular trafficking. Proteomic analyses further identified intracellular , an AD risk gene, as significantly upregulated in OPTN KO iNs, suggesting OPTN may influence its intracellular processing. Our model system demonstrates modest roles for OPTN in certain neuronal biological processes and potential implications for AD pathogenesis. These findings also suggest that OPTN may exhibit functional redundancy with other autophagy adaptor proteins in human neurons, leading to relatively mild phenotypic changes with complete loss of OPTN.

Key numbers

Increase in

Specific levels increased in KO neurons.

significant

Upregulation of intracellular

Intracellular levels were significantly increased in KO neurons.

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Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons

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