Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease

Ambaw, Abeje; Zheng, Lingxing; Tambe, Mitali A.; Strathearn, Katherine E.; Acosta, Glen; Hubers, Scott A.; Liu, Fang; Herr, Seth A.; Tang, Jintao; Truong, Alan; Walls, Elwood K.; Pond, Amber; Rochet, Jean‐Christophe; Shi, Riyi

doi:10.1016/j.mcn.2018.01.006

Cited by 42 publications

(44 citation statements)

References 71 publications

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“…Although α-Syn deposits are primarily found in neurons in the PD brain, they also appear frequently in astrocytes [ 12 , 13 ]. Besides directly damaging mitochondria and lysosome of neurons, the increased level of α-Syn also causes glial response and the reactive glia release inflammatory mediators such as reactive oxygen species, nitric oxide, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) [ 14 , 15 ]. They are the main causes of synaptic dysfunction and neuronal death, leading to a self-amplifying cycle of inflammation, and eventually accelerate the process of PD [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

Zhou

Xia

et al. 2018

J Neuroinflammation

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Backgroundα-Synuclein (α-Syn)-induced neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of neurodegenerative diseases. However, the effect of astrocytic Drd2 in α-Syn-induced neuroinflammation remains unclear.MethodsThe effect of Drd2 on neuroinflammation was examined in mouse primary astrocyte in vitro and A53T transgenic mice in vivo. The inflammatory responses of astrocyte were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting and protein-protein interaction assays.ResultsWe showed that the selective Drd2 agonist quinpirole suppressed inflammation in the midbrain of wild-type mice, but not in α-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress α-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on β-arrestin2-mediated signaling, but not classical G protein pathway. α-Syn reduced the expression of β-arrestin2 in astrocytes. Increased the β-arrestin2 expression restored in the anti-inflammation of Drd2 in α-Syn-induced inflammation. Furthermore, we demonstrated that α-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of β-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and promoting TAK1-TAB1 interaction in astrocytes.ConclusionsOur study illustrates that astrocytic Drd2 inhibits neuroinflammation through a β-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that α-Syn disrupts the function of β-arrestin2 and inflammatory pathways in the pathogenesis of PD.

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Section: Introductionmentioning

confidence: 99%

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

Zhou

Xia

et al. 2018

J Neuroinflammation

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“…As imilar trend has been previously reported in the presence of ACR but also in the case of nitrated forms of aSyn. [22,41,43] In particular,t he formation of aSyn species corresponding to aSyn dimers and trimers in the presenceo fA CR have been observed by western-blot analysis of both in vitro and in vivo samples. [21][22][23] These small oligomers could cause the inhibition of the fibrillation similar to other dimers of aSyn.…”

Section: Acr and Cu 2 + + Affect Asyn Aggregationmentioning

confidence: 99%

“…[22,41,43] In particular,t he formation of aSyn species corresponding to aSyn dimers and trimers in the presenceo fA CR have been observed by western-blot analysis of both in vitro and in vivo samples. [21][22][23] These small oligomers could cause the inhibition of the fibrillation similar to other dimers of aSyn. [44] Instead, the addition of Cu 2 + to a aSyn solution instantly causedt he formation of as mall percentage of aggregates with am ean diameter of 44 AE 3nm( Figure S13).…”

Section: Acr and Cu 2 + + Affect Asyn Aggregationmentioning

confidence: 99%

“…In particular, ACR and HNEh ave been reported to affect the aggregation process of aSyn. [20][21][22][23][24][25] The adducts between aSyn and HNE have been extensively characterized by in vitro experiments, and His50 was identified as the main modification site. [26,27] Notwithstanding these findings, the adducts ACR-aSyn have been less exploreda nd characterized.…”

Section: Introductionmentioning

confidence: 99%

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Acrolein and Copper as Competitive Effectors of α‐Synuclein

Falcone

Ahmed

Oliveri

et al. 2020

Chemistry A European J

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Mounting evidences upports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by a-synuclein (aSyn) accumulation and aggregation in brain regions,a lso promoted by Cu 2 + . aSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper,a nd aSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on aSyn using an approach based on LC-MS/MS analy-sis. We also evaluated the influence of Cu 2 + on the protein carbonylation and how the ACR modification impacts the Cu 2 + binding and the production of Reactive OxygenS pecies (ROS). Finally,w ei nvestigated the effects of ACR and Cu 2 + ions on the aSyn aggregation by dynamic light scattering and fluorescencea ssays. Cu 2 + regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu 2 + and ACR inhibits aSyn aggregation both in the presence and in the absence of Cu 2 + .Supporting information and the ORCID identification numbers for the authors of this article can be found under: https://doi.

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“…[17][18][19] The α,β-unsaturated aldehydes can form adducts with nucleophilic residues of proteins by two different mechanisms: (1) Michael addition at the double bond to Lys, His or Cys residues or (2) Schiff base formation of the carbonyl group to Lys residues. 12,14 Lipid-derived aldehydes have already been shown to modify several proteins, 20,21 including those related to neurodegenerative diseases: αsynuclein, [22][23][24][25] β-amyloid peptide 26,27 and superoxide dismutase (SOD1). 28 Cholesterol is another lipid present in massive amounts in neurons and glial cells.…”

Section: Introductionmentioning

confidence: 99%

Lipid-derived electrophiles induce covalent modification and aggregation of Cu,Zn-superoxide dismutase in a hydrophobicity-dependent manner

Dantas

Viviani²,

Inague

et al. 2019

Preprint

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Lipid peroxidation generates a huge number of reactive electrophilic aldehyde products.These reactive aldehydes can modify macromolecules such as proteins, resulting in loss of function and/or aggregation. The accumulation of Cu,Zn-superoxide dismutase (SOD1) aggregates is associated with familial cases of amyotrophic lateral sclerosis (ALS). Recent studies have shown that lipid and its oxidized derivatives may play a role in this process. Here we aimed to compare and characterize the ability of lipid-derived electrophiles with different hydrophobicities to induce SOD1 modification and aggregation in vitro. SOD1 was incubated with 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE), 2-hexen-1-al (HEX), 2,4-nonadienal (NON), 2,4-decadienal (DEC) or secosterol aldehydes (Seco-A or Seco-B) at 37°C for 24 h. Size exclusion chromatography analysis showed that hydrophobic aldehydes markedly enhances apo-SOD1 aggregation. More importantly, aggregation level was positively correlated to calculated aldehyde hydrophobicities (LogP). Protein sequencing by LC-MS/MS showed that aldehydes covalently modifies SOD1 at aggregation prone regions. For instance, specific lysine residues located mainly nearby the dimer interface (K3, K9) and at the electrostatic loop (K122, K128, K136) were ubiquitously modified by all aldehydes. The a,b-unsaturated aldehydes also promoted modifications on histidine and cysteine residues, with H120 and C6 being the most commonly modified residues. Overall, our data suggest that electrophile`s hydrophobicity is a critical factor that strongly influences protein aggregation propensity.

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Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease

Cited by 42 publications

References 71 publications

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

Acrolein and Copper as Competitive Effectors of α‐Synuclein

Lipid-derived electrophiles induce covalent modification and aggregation of Cu,Zn-superoxide dismutase in a hydrophobicity-dependent manner

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