The Cytotoxic Effect of α‐Synuclein Aggregates

Melo, Francisco; Caballero, Leonardo; Zamorano, Esteban; Ventura, Natalia; Navarro, Camilo; Doll, Irving; Zamorano, Pedro; Cornejo, Alberto

doi:10.1002/cphc.202000831

Cited by 7 publications

(5 citation statements)

References 31 publications

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“…Aggregation of proteins into toxic species is a hallmark of many diseases known as proteinopathies, including the amyloid-β (Aβ) peptides and tau proteins in AD [43], the α-synuclein (α-Syn) protein in Parkinson's disease [44,45], the prion (PrP) protein in Creutzfeldt-Jakob disease [46,47] and the huntingtin protein in Huntington's disease [48]. In vivo, the protein aggregates can be detected after staining with a dye or other biomarker.…”

Section: Introductionmentioning

confidence: 99%

“…A common structural motif in the fibrillar aggregates is the "cross-β structure", which consists of repeated units of β-strands positioned perpendicular to the fibril axis, stabilised by inter-strand hydrogen bonds aligned along the direction of the fibril axis [54,55]. The main toxic species in many proteinopathies appears not to be the large protein aggregates but rather small soluble intermediate oligomers that form along the aggregation pathways [44,46,48,56]. Being important potential drug targets, these oligomers have been extensively researched, but their sizes, shapes and structures remain unclear [49].…”

Section: Introductionmentioning

confidence: 99%

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Metals in ALS TDP-43 Pathology

Koski

Ronnevi

Berntsson

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metals in ALS TDP-43 Pathology

Koski

Ronnevi

Berntsson

et al. 2021

IJMS

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“…Once we labeled the cells incubated with aggregates formed by tau and α‐syn peptide, the staining also appeared as dots and blobs suggesting the presence of aggregates in the periphery (Figure 5 B–C). Previously, we demonstrated that α‐syn aggregates can promote cell death by diminishing the cohesion of the membrane of cells, [34] , thus we decided to test the cells against these types of aggregates by staining the samples with DAPI and using the phase to check the cells and nuclei morphologies, respectively. In control cells, (Figure 6A) the morphology showed cells with neurite‐like structures after retinoic acid induction and a regular chromatin distribution in the nucleus.…”

Section: Resultsmentioning

confidence: 99%

α‐Synuclein Drives Tau's Cytotoxic Aggregates Formation through Hydrophobic Interactions

Ojeda,

Cofré,

Melo

et al. 2023

ChemPlusChem

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Tau and α‐synuclein are proteins involved in pathologies known as tauopathies and synucleinopathies, respectively. Moreover, evidence shows that there is a crosstalk between them as is seen in the brains of individuals with sporadic neurodegenerative disorders. Based on that, we present data showing that the hydrophobic α‐peptide 71VTGVTAVAQKTV82 induces the aggregation of the full‐length tau fragment in the absence of heparin assessed by ThT. Moreover, AFM images reveal the presence of straight filaments and amorphous aggregates of full‐length tau in the presence of the α‐peptide. Additionally, ITC experiments showed the interaction of the α‐peptide with tau full‐length (441),4R (244‐369), and both hexapeptides 275VQIINK280 and 306VQIVYK311 through hydrophobic interactions. The Raman spectroscopy spectra showed conformational changes in the Amide region in the aggregates formed with full‐length tau and α‐syn peptide. Furthermore, the incubation of extracellular aggregates with N2a cells showed morphological differences in the cellular body and the nucleus. Also, the incubation of different types of aggregates in cell culture provokes the release of Lactate dehydrogenase (LDH). Altogether, we found that α‐synuclein peptide can drive the aggregation of full‐length tau‐provoking morphological and structural changes evoking cytotoxic effects.

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“…Lipid membrane fluidity is essential for the efficient binding of alpha-synuclein [156]. If aberrant lipid homeostasis occurs, this may alter the lipid membrane composition or fluidity and the binding of alpha-synuclein, leading to subsequent neurotoxicity [114,157,158]. Alterations in the lipid composition have been reported in PD brains, including changes in levels of fatty acids and the lipid raft content [159].…”

Section: Lipid Homeostasismentioning

confidence: 99%

GBA Variants and Parkinson Disease: Mechanisms and Treatments

Smith

Schapira

2022

Cells

109

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The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

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The Cytotoxic Effect of α‐Synuclein Aggregates

Cited by 7 publications

References 31 publications

Metals in ALS TDP-43 Pathology

Metals in ALS TDP-43 Pathology

α‐Synuclein Drives Tau's Cytotoxic Aggregates Formation through Hydrophobic Interactions

GBA Variants and Parkinson Disease: Mechanisms and Treatments

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