The phospholipase D1 pathway modulates macroautophagy

Dall’Armi, Claudia; Hurtado-Lorenzo, Andrés; Huang, Tian; Morel, Étienne; Nezu, Akihiro; Chan, Robin B.; Yu, Wen H.; Robinson, Kimberly; Yeku, Oladapo; Small, Scott A.; Duff, Karen; Frohman, Michael A.; Wenk, Markus R.; Yamamoto, Akira; Paolo, Gilbert Di

doi:10.1038/ncomms1144

Cited by 150 publications

(146 citation statements)

References 56 publications

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“…Inhibition of PLD1 activity and reduction in PLD1 expression resulted in excessive accumulation of APs with substrates such as p62, polyubiquitinated proteins, and a-synuclein aggregates inside, whereas autolysosomes were reduced under the same conditions. Our findings are consistent with the previous study by Dall'Armi et al, 16 where PLD1 was predominantly associated with endosomes in normal growth medium and translocated to the limiting membranes of the amphisomes during starvation-induced autophagy.…”

Section: Discussionsupporting

confidence: 94%

“…Our results are consistent with the previous study where pharmacological inhibition of PLD led to an increase in detergent-insoluble tau in brain slice culture. 16 Our study further validated the importance of PLD1 by showing that accumulation of a-synuclein aggregates and concomitant cytotoxicity were reversed by ectopic expression of the wild-type PLD1, but not by the expression of an activity-deficient mutant PLD1. Therefore, maintaining the normal levels of PLD activity may be critical to cellular protein homeostasis, and thus to preventing neuronal cells from degeneration.…”

Section: Discussionsupporting

confidence: 73%

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Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

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Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, a-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of a-synuclein aggregates in autophagosomes. Neuronal toxicity caused by a-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of a-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 73%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

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“…5). This raises important questions about how PLD and its product PA are related to ganglioside metabolism and perhaps endolysosomal dysregulation in AD (11,50). Additionally, because PLD 2 ablation mitigates the signaling, but not the biogenesis of A␤ (11), we hypothesize that the GM3 elevation observed in the APP models (which is corrected in the Pld2 knock-out) occurs downstream of A␤.…”

Section: Discussionmentioning

confidence: 99%

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Chan

Oliveira

Cortés

et al. 2012

Journal of Biological Chemistry

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“…However, knock-out of both PLD1 and PLD2 yields viable mice (32,33), whereas mTOR knockouts are embryonic lethal (34,35). Thus, the PA needed to keep mTOR intact and active must be generated from sources other than the hydrolysis of phosphatidylcholine by PLD.…”

Section: Sources Of Pamentioning

confidence: 99%

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Foster

Salloum

Menon

et al. 2014

Journal of Biological Chemistry

105

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Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.

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The phospholipase D1 pathway modulates macroautophagy

Cited by 150 publications

References 56 publications

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

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