Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death

Mader, Burton J.; Pivtoraiko, Violetta N.; Flippo, Hilary M; Klocke, Barbara J.; Roth, Kevin A.; Mangieri, Leandra R.; Shacka, John J.

doi:10.1021/cn300145z

Cited by 93 publications

(79 citation statements)

References 40 publications

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“…Thus, our data showing LC3 colocalization strongly suggest puncta stem from autophagic vesicles, instead of aberrant OPTN degradation (Shen et al, 2011). Overall, our findings are consistent with the observations that autophagy is impaired in PD brains and models, where alpha-synuclein accumulation has been intensely investigated (Mader et al, 2012;Tan et al, 2014). Alpha-synuclein is a pivotal PD protein linked to the pathogenesis and progression of sporadic and genetic PD (Braak et al, 2004;Polymeropoulos et al, 1997;Spillantini et al, 1997).…”

Section: Discussionsupporting

confidence: 90%

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

Wise

Cannon

2016

Toxicol. Sci.

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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.

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Section: Discussionsupporting

confidence: 90%

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

Wise

Cannon

2016

Toxicol. Sci.

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“…It is likely that the effect on autophagy already evidenced in this study at 6 h can be due to the higher rotenone concentration used. Moreover, monitoring the autophagic flux revealed that the increase of autophagic vacuoles is due to a block of the lysosomal degradation rather than an autophagy induction [143]. This finding is in line with the knowledge that rotenone exposure causes an accumulation of PD-related proteins, such as -synuclein.…”

Section: Dysfunctions Of Macroautophagy Induced By Rotenonesupporting

confidence: 86%

Exploring the Role of Autophagy in the Pathogenesis of Rotenone-induced Toxicity

Sala

Stefanoni

Marinig

et al. 2015

Current Topics in Neurotoxicity

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This chapter is intended to provide an organic revision of evidence for the involvement of autophagy in the pathogenesis of rotenone-induced toxicity. The mechanisms underlying rotenone neurotoxicity are elucidated through a description of findings obtained in both in vivo and in vitro experimental models. Furthermore, this chapter describes the etiological role of rotenone and other pesticide exposure in the pathogenesis of Parkinson's disease, as demonstrated by epidemiological studies performed in the last decades starting from results obtained in animal and cellular experimental models. The specific focus of the present chapter is to explore the effect of rotenone on autophagic pathway, whose dysfunctions are already recognized to play an important pathogenetic role in Parkinson's disease. Specifically, a comprehensive revision of the current available literature on the rotenone-induced dysfunctions of the two main types of autophagy, macroautophagy and chaperonemediated autophagy, is provided in order to clarify the protective rather than detrimental contribute exerted by autophagy alterations in the cell death induced by rotenone.

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“…The implications of the ATP13A2 lipid interactions were evaluated in a well-established cellular PD disease model of mitochondrial complex I inhibition by rotenone to evoke mitochondrial stress (22,23). Rotenone reduced cell viability in all cell lines (Fig.…”

Section: Lipid-mediated Atp13a2 Activity Confers Protection In a Cellmentioning

confidence: 99%

A lipid switch unlocks Parkinson’s disease-associated ATP13A2

Holemans

Sørensen

Veen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

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ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against α-synuclein, Mn 2+ , and Zn 2+ toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2]. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5)P2. Thus, the N-terminal binding of PA and PI(3,5)P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce α-synuclein toxicity or mitochondrial stress in PD or related disorders.mitochondria | lysosome | flippase | α-synuclein | P5-type ATPase N euronal fitness depends on optimal lysosomal function and efficient lysosomal delivery of proteins and organelles by autophagy for subsequent breakdown (1, 2). Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) associated with dementia, which is caused by mutations in ATP13A2/PARK9 (3). Mutations in or knockdown (KD) of ATP13A2 lead to lysosomal dysfunctions, including reduced lysosomal acidification, decreased degradation of lysosomal substrates (4), impaired autophagosomal flux (4, 5), and accumulation of fragmented mitochondria (5, 6). By contrast, overexpression (OE) of Ypk9p (i.e., the yeast ATP13A2 ortholog) protects yeast against toxicity of α-synuclein (7), which is the major protein in Lewy bodies, the abnormal protein aggregates that develop inside nerve cells in PD. This protective effect of ATP13A2 on α-synuclein toxicity is conserved in yeast, Caenorhabditis elegans, and rat neuronal cells (7). Because ATP13A2 imparts resistance to Mn 2+ (7-9) and Zn 2+ (10-12), it was proposed that ATP13A2 may function as a Mn 2+ (7-9) and/or Zn 2+ transporter (10-12).ATP13A2 belongs to the P5 subfamily of the P-type ATPase superfamily, which comprises five subfamilies (P1-5) of membrane transporters. P-type ATPases hydrolyze ATP to actively transport inorganic ions across membranes or lipids between membrane leaflets (reviewed in ref. 13). During the transport cycle, a phosphointermediate is formed on a conserved aspartate residue (14). The human P5-type ATPases are divided into two groups, P5A (ATP13A1) and P5B (ATP13A2-5), but their transport specificity has not been established (14-16).P-type ATPases comprise a membrane-embedded core of six transmembrane (TM) helices (M1-6) that form the substrate binding site(s) and entrance/exit pathways for the transp...

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Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death

Cited by 93 publications

References 40 publications

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

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

Exploring the Role of Autophagy in the Pathogenesis of Rotenone-induced Toxicity

A lipid switch unlocks Parkinson’s disease-associated ATP13A2

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