From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

Abstract

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 þ 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.

Autophagy Disruptions Associated With Altered Optineurin Expression in Extranigral Regions in a Rotenone Model of Parkinson's Disease

“…The main goal here was to examine autophagic disruptions in brain nuclei linked to non-motor PD symptoms in response to treatment with rotenone, a known mitochondrial toxin used to model PD. With the temporal development of the lesion already published in these animals and also extensively characterized in other studies (Cannon et al, 2009 ; Wise and Cannon, 2016 ), we are able to determine if changes in other brain regions precede an overt lesion to the nigrostriatal dopamine system.…”

“…Detailed methodology is described below. However, it is worth noting that the exact animals utilized in this study have been well-characterized for lesion development in the nigrostriatal dopamine system and autophagic disruption in dopaminergic neurons (Wise and Cannon, 2016 ). None of the analyses in that publication overlap with this report, which has a different set of experimental goals.…”

“…In this model, overt behavioral deficits are associated with a lesion to the nigrostriatal dopamine system (Betarbet et al, 2000 ; Cannon et al, 2009 ), while sampling at 5 days or before is prior to the development of an detectable lesion (Sanders et al, 2014a , b ). Of note, the temporal development of a nigrostriatal dopamine system has been characterized in the animals used in this report (Wise and Cannon, 2016 ).…”

“…We analyzed changes to expression and punctate forms of OPTN and LC3 in four nuclei implicated in Braak's hypothesis of PD: the dorsal motor vagal nucleus (10N), magnocellular raphe (RMg), locus coeruleus (LC), pedunculopontine tegmentum nucleus (PTg). We also considered changes to expression of alpha-synuclein and beclin-1 in the substantia nigra pars compacta (SNpc) because we previously showed that OPTN and LC3 expression and puncta were altered in this brain region (Wise and Cannon, 2016 ). These regions were chosen because they are implicated in Braak's hypothesis of Lewy body progression in PD and they are linked to many PD nonmotor symptoms (Braak et al, 2003 ; Wolters, 2009 ).…”

“…Intriguingly, the glaucomatic OPTN M98K mutation was found to be a risk factor for PD in a recent genome wide association study, and PD patients exhibit a higher prevalence of developing glaucoma (Lill et al, 2012 ; Nucci et al, 2015 ; Sirohi et al, 2015 ). We previously demonstrated OPTN is robustly expressed in nigral dopamine neurons, and its expression and interaction with LC3 is elevated after rotenone exposure in rats (Wise and Cannon, 2016 ). However, expression in other brain nuclei and changes in such expression in PD models are unknown.…”