From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models
Open accessAbstract
Parkinson's disease (PD) is a progressive neurodegenerative disease that affects ∼5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN(+ )aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis.
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The authors identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1.
“In a first case, starting from experimental data available in the literature, we identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1 (Fig. 2) [18–27].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [23]
The section “Rotenone Alters OPTN Expression in Relation to Autophagic Activity and alpha-Synuclein Puncta” (page unavailable) links OPTN and LC3 to autophagy, supporting their inclusion as targets drawn from the literature. Our copy does not establish the full list of 20 targets. The qPCR validation is described as the citing authors’ own work, not as a finding of this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe activation list was derived from comparison of publications reporting conditions of gene up-regulation upon autophagy activation.
“A so called “activation list” has been derived from the comparison of publications, in which we reported conditions of gene up-regulation upon autophagy activation [18–27].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [23]
The Results section ('Rotenone Alters OPTN Expression in Relation to Autophagic Activity and alpha-Synuclein Puncta'; page unavailable) reports OPTN and LC3 protein expression in rotenone-treated rats. Searches for an activation list and for gene up-regulation upon autophagy activation found no passage describing a list derived by comparing publications. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe restricted "induction list" for the prediction of autophagy activation state is made of 20 targets and was obtained by combining data from previous publications documenting increased mRNA expression following autophagy induction.
“The restricted “induction list” for the prediction of autophagy activation state, made by 20 targets, was obtained combining data from previous publications [18–27], in which have been documented the increase of the mRNA expression following autophagy induction.”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [23]
The Results section, “Rotenone Alters OPTN Expression in Relation to Autophagic Activity and alpha-Synuclein Puncta” (page unavailable), reports OPTN protein staining and its localization in rotenone-treated rats. A search for mRNA expression after autophagy induction and for a 20-target induction list found no passage in our copy addressing either point. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Korac, J., Schaeffer, V., Kovacevic, I., Clement, A. M., Jungblut, B., Behl, C., Terzic, J., & Dikic, I. (2013) · Journal of Cell Science · doi:10.1242/jcs.114926 · Cited by 336 · see citing works
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Research works printed but not linked: 3
- Cannon, J. R., and Greenamyre, J. T. (2014). Rotenone as preclini- cal model compound in Parkinson disease. In Handbook of Neurotoxicity (R. M. Kostrzewa, Ed.), pp. 995-1012. Springer, New York, NY.
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A gene toolbox for monitoring autophagy transcription
Bordi, M., De Cegli, R., Testa, B., Nixon, R. A., Ballabio, A., & Cecconi, F. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-04121-9 · Cited by 131 · see citing works
- Authors
- Wise, J. P., & Cannon, J.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Cannon, Jason
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-07-29
- Volume
- 153
- Issue
- 2
- Pages
- 372-381
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC5036620
- OpenAlex
- W2525090071
- Cited by
- 20
- References
- 3
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 1 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 4
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (R01ES025750, R00ES019879, R03ES022819)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- optineurin, Parkinson's disease, rotenone, autophagy, dopaminergic neurons, midbrain, alpha-synuclein, LC3, neurodegeneration, nigrostriatal pathway, preclinical disease models, protein localization
- MeSH terms
- Animals, Autophagy, Corpus Striatum, Disease Models, Animal, Mesencephalon, Parkinson Disease, Rats, Inbred Lew, Rotenone, Substantia Nigra, Cell Cycle Proteins, Membrane Transport Proteins, Transcription Factor TFIIIA, Rats, alpha-Synuclein
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