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Emerging roles for lipids in non-apoptotic cell death.

ABSTRACT: Non-apoptotic regulated cell death (RCD) is essential to maintain organismal homeostasis and may be aberrantly activated during certain pathological states. Lipids are emerging as key components of several non-apoptotic RCD pathways. For example, a direct interaction between membrane phospholipids and the pore-forming protein mixed lineage kinase domain-like (MLKL) is needed for the execution of necroptosis, while the oxidative destruction of membrane polyunsaturated fatty acids (PUFAs), following the inactivation of glutathione peroxidase 4 (GPX4), is a requisite gateway to ferroptosis. Here, we review the roles of lipids in the initiation and execution of these and other forms of non-apoptotic cell death. We also consider new technologies that are allowing for the roles of lipids and lipid metabolism in RCD to be probed in increasingly sophisticated ways. In certain cases, this new knowledge may enable the development of therapies that target lipids and lipid metabolic processes to enhance or suppress specific non-apoptotic RCD pathways.

SUBMITTER: Magtanong L

PROVIDER: S-EPMC5399169 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Emerging roles for lipids in non-apoptotic cell death.

Magtanong L L Ko P J PJ Dixon S J SJ

Cell death and differentiation 20160311 7

Non-apoptotic regulated cell death (RCD) is essential to maintain organismal homeostasis and may be aberrantly activated during certain pathological states. Lipids are emerging as key components of several non-apoptotic RCD pathways. For example, a direct interaction between membrane phospholipids and the pore-forming protein mixed lineage kinase domain-like (MLKL) is needed for the execution of necroptosis, while the oxidative destruction of membrane polyunsaturated fatty acids (PUFAs), followi ...[more]

PMID: 26967968

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Project description:The role of extracellular ?-synuclein (?-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the ?-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric ?-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric ?-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, ?-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric ?-syn. The causal relationship between ?-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on ?-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of ?-syn fibrillization (Tolcapone) or replacing monomeric ?-syn by monomeric ?-synuclein in ?-syn mixture composition prevent ?-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added ?-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of ?-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular ?-syn play central roles in ?-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against ?-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies.

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Emerging roles for lipids in non-apoptotic cell death.

Publications

Emerging roles for lipids in non-apoptotic cell death.

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