The Role of Lipids in the Initiation of α-Synuclein Misfolding

Kiechle, Martin; Grozdanov, Veselin; Danzer, Katrin M.

doi:10.3389/fcell.2020.562241

Cited by 34 publications

(30 citation statements)

References 103 publications

(111 reference statements)

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“…An involvement of synucleins in the modulation of lipid metabolism has been shown by numerous studies [ 40 , 41 , 42 , 43 , 44 , 48 ]. Special attention has been paid to the complex interactions between lipids (fatty acids and membrane lipids) and synucleins, which have been briefly outlined in the Introduction.…”

Section: Discussionmentioning

confidence: 99%

“…through complex interplaying and overlapping mechanisms. As an interplay, numerous recorded changes in lipids (and lipid metabolism in cells and various synuclein mouse models) were associated to either the synuclein loss-of-function or a toxic gain-of-function hypothesis [ 40 , 41 , 42 , 43 , 44 ]. In summary, they include: uptake of fatty acids into cells; changes in brain cardiolipin and its fatty acid acyl chains [ 2 ]; an increased level of brain triacylglycerol (TAG) content in α-synuclein mouse mutant model associated with increased fatty acid synthase expression and acyl-CoA synthase activity, with no variations in TAG lipase activity or in fatty acid β-oxidation [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

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Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

et al. 2021

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Recent studies have implicated synucleins in several reactions during the biosynthesis of lipids and fatty acids in addition to their recognised role in membrane lipid binding and synaptic functions. These are among aspects of decreased synuclein functions that are still poorly acknowledged especially in regard to pathogenesis in Parkinson’s disease. Here, we aimed to add to existing knowledge of synuclein deficiency (i.e., the lack of all three family members), with respect to changes in fatty acids and lipids in plasma, liver, and two brain regions in triple synuclein-knockout (TKO) mice. We describe changes of long-chain polyunsaturated fatty acids (LCPUFA) and palmitic acid in liver and plasma, reduced triacylglycerol (TAG) accumulation in liver and non-esterified fatty acids in plasma of synuclein free mice. In midbrain, we observed counterbalanced changes in the relative concentrations of phosphatidylcholine (PC) and cerebrosides (CER). We also recorded a notable reduction in ethanolamine plasmalogens in the midbrain of synuclein free mice, which is an important finding since the abnormal ether lipid metabolism usually associated with neurological disorders. In summary, our data demonstrates that synuclein deficiency results in alterations of the PUFA synthesis, storage lipid accumulation in the liver, and the reduction of plasmalogens and CER, those polar lipids which are principal compounds of lipid rafts in many tissues. An ablation of all three synuclein family members causes more profound changes in lipid metabolism than changes previously shown to be associated with γ-synuclein deficiency alone. Possible mechanisms by which synuclein deficiency may govern the reported modifications of lipid metabolism in TKO mice are proposed and discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

et al. 2021

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“…Together with the lipid composition, the lipid to protein ratio is a discriminant factor for amyloidogenesis, being able to switch the equilibrium between physiological and pathological paths, as first described by Galvagnion et al (2015) and later discussed in a detailed review by Kiechle et al (2020) . When this value is high, due to the low local concentration of αSyn, the aggregation can be suppressed.…”

Section: Effect Of the Biological Environment On αSyn Structural Featuresmentioning

confidence: 99%

α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques

et al. 2021

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Alpha-synuclein (αSyn) is a highly expressed and conserved protein, typically found in the presynaptic terminals of neurons. The misfolding and aggregation of αSyn into amyloid fibrils is a pathogenic hallmark of several neurodegenerative diseases called synucleinopathies, such as Parkinson’s disease. Since αSyn is an Intrinsically Disordered Protein, the characterization of its structure remains very challenging. Moreover, the mechanisms by which the structural conversion of monomeric αSyn into oligomers and finally into fibrils takes place is still far to be completely understood. Over the years, various studies have provided insights into the possible pathways that αSyn could follow to misfold and acquire oligomeric and fibrillar forms. In addition, it has been observed that αSyn structure can be influenced by different parameters, such as mutations in its sequence, the biological environment (e.g., lipids, endogenous small molecules and proteins), the interaction with exogenous compounds (e.g., drugs, diet components, heavy metals). Herein, we review the structural features of αSyn (wild-type and disease-mutated) that have been elucidated up to present by both experimental and computational techniques in different environmental and biological conditions. We believe that this gathering of current knowledge will further facilitate studies on αSyn, helping the planning of future experiments on the interactions of this protein with targeting molecules especially taking into consideration the environmental conditions.

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“…Therefore, various metals and bioactive lipids cooperatively modulate the protein biological properties in neurogenerative diseases. The oligomer formation of proteins is regulated by lipids and metals [ 157 , 158 ]. An excess number of metals may directly induce lipid peroxidation and protein oxidation followed by neurodegeneration, and the modulation of levels of metals may indirectly have a protective effect against lipid peroxidation via NRF2 activation.…”

Section: Manipulation Of Neurodegeneration By Anti-oxidative Chemicals and Enzymesmentioning

confidence: 99%

Cell Death via Lipid Peroxidation and Protein Aggregation Diseases

Iuchi

Takai

Higuchi

2021

Biology

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Lipid peroxidation of cellular membranes is a complicated cellular event, and it is both the cause and result of various diseases, such as ischemia-reperfusion injury, neurodegenerative diseases, and atherosclerosis. Lipid peroxidation causes non-apoptotic cell death, which is associated with cell fate determination: survival or cell death. During the radical chain reaction of lipid peroxidation, various oxidized lipid products accumulate in cells, followed by organelle dysfunction and the induction of non-apoptotic cell death. Highly reactive oxidized products from unsaturated fatty acids are detected under pathological conditions. Pathological protein aggregation is the general cause of these diseases. The cellular response to misfolded proteins is well-known as the unfolded protein response (UPR) and it is partially concomitant with the response to lipid peroxidation. Moreover, the association between protein aggregation and non-apoptotic cell death by lipid peroxidation is attracting attention. The link between lipid peroxidation and protein aggregation is a matter of concern in biomedical fields. Here, we focus on lethal protein aggregation in non-apoptotic cell death via lipid peroxidation. We reviewed the roles of protein aggregation in the initiation and execution of non-apoptotic cell death. We also considered the relationship between protein aggregation and oxidized lipid production. We provide an overview of non-apoptotic cell death with a focus on lipid peroxidation for therapeutic targeting during protein aggregation diseases.

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The Role of Lipids in the Initiation of α-Synuclein Misfolding

Cited by 34 publications

References 103 publications

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques

Cell Death via Lipid Peroxidation and Protein Aggregation Diseases

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