Functional Analysis of VPS41-Mediated Neuroprotection in<i>Caenorhabditis elegans</i>and Mammalian Models of Parkinson's Disease

Harrington, Adam J.; Yacoubian, Talene A.; Slone, Sunny R.; Caldwell, Kim A.; Caldwell, Guy A.

doi:10.1523/jneurosci.2606-11.2012

Cited by 71 publications

(112 citation statements)

References 41 publications

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“…Until recently, dopaminergic neurons in C. elegans have been found to be recalcitrant to RNAi. However, there are now methods available that enable neuronal-sensitive RNAi (34 (35,36). Using these dopaminergic-specific RNAi strains of C. elegans, we knocked down psd-1 and analyzed dopaminergic neurodegeneration in worm populations (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The dopaminergic neurons in the F1 progeny of the RNAitreated worms were analyzed for neurodegeneration at days 6 and 7. Two strains of C. elegans that provide cell-specific RNAi in dopaminergic neurons (35) were used in this study. Strain UA196 [sid-1(pk3321); Pdat-1::α-syn, Pdat-1::GFP; Pdat-1::sid-1, and Pmyo-2::mCherry] expresses α-syn, GFP, and SID-1 in the dopaminergic neurons and is susceptible to RNAi selectively in dopaminergic neurons.…”

Section: Methodsmentioning

confidence: 99%

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Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Wang¹,

Zhang

Liou

et al. 2014

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

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Significance We tested the hypothesis that a form of mitochondrial dysfunction alters the homeostasis of the cytosolic Parkinson disease (PD)-associated protein α-synuclein (α-syn). Using yeast and worm models of PD, we show that low levels of phosphatidylethanolamine (PE), caused by the depletion of mitochondrial phosphatidylserine decarboxylase (psd), lead to decreased respiration, endoplasmic reticulum (ER) stress, high levels of α-syn and cytoplasmic α-syn foci, and slow growth. Ethanolamine, which replenishes PE through the Kennedy pathway, diminished ER stress, decreased the level of α-syn, eliminated foci, and restored growth of psd1 Δ cells to near wild-type levels. A low level of mitochondrial PE disrupts the homeostasis of α-syn and leads to the accumulation of cytoplasmic foci of this protein.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Wang¹,

Zhang

Liou

et al. 2014

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

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“…Deletion or mutations of HOPS subunits deep orange (VPS18 homologue), carnation (VPS33a homologue) or dvps16A (VPS16 homologue) result in defective late endosomal and lysosomal biogenesis in Drosophila melanogaster (Pulipparacharuvil et al, 2005;Sevrioukov et al, 1999). Mutations in VPS41 can protect against a-synuclein-induced neurotoxicity in C. elegans and Parkinson's disease in mammalian model systems (Harrington et al, 2012;Ruan et al, 2010), and VPS41-deficient mouse embryos fail to develop beyond the gastrulation stage (Aoyama et al, 2012). In addition, the HOPS complex has been implicated in Ebola virus infection, EGFR trafficking, autophagolysosome formation and endosomal peptide loading of CD1d (Carette et al, 2011;Ganley et al, 2011;Chirivino et al, 2011;Garg et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L

Kant

Fish

Janssen

et al. 2013

Journal of Cell Science

166

161

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SummaryLate endosomes and lysosomes are dynamic organelles that constantly move and fuse to acquire cargo from early endosomes, phagosomes and autophagosome. Defects in lysosomal dynamics cause severe neurodegenerative and developmental diseases, such as Niemann-Pick type C disease and ARC syndrome, yet little is known about the regulation of late endosomal fusion in a mammalian system. Mammalian endosomes destined for fusion need to be transported over very long distances before they tether to initiate contact. Here, we describe that lysosomal tethering and transport are combined processes co-regulated by one multi-protein complex: RAB7-RILP-ORP1L. We show that RILP directly and concomitantly binds the tethering HOPS complex and the p150Glued subunit of the dynein motor. ORP1L then functions as a cholesterol-sensing switch controlling RILP-HOPS-p150Glued interactions. We show that RILP and ORP1L control Ebola virus infection, a process dependent on late endosomal fusion. By combining recruitment and regulation of both the dynein motor and HOPS complex into a single multiprotein complex, the RAB7-RILP-ORP1L complex efficiently couples and regulates the timing of microtubule minus-end transport and fusion, two major events in endosomal biology.

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“…RCN-1 overexpression and quantitation C. elegans was performed as described (34). RNA interference (RNAi) in C. elegans was performed as described (33). CaM mutants were performed by QuikChange XL site-directed mutagenesis as described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Calcineurin determines toxic versus beneficial responses to α-synuclein

Caraveo

Auluck

Whitesell

et al. 2014

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

105

144

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Calcineurin (CN) is a highly conserved Ca 2+ -calmodulin (CaM)-dependent phosphatase that senses Ca 2+ concentrations and transduces that information into cellular responses. Ca 2+ homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca 2+ , thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

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Functional Analysis of VPS41-Mediated Neuroprotection inCaenorhabditis elegansand Mammalian Models of Parkinson's Disease

Cited by 71 publications

References 41 publications

Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L

Calcineurin determines toxic versus beneficial responses to α-synuclein

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