Polarized α-synuclein trafficking and transcytosis across brain endothelial cells via Rab7-decorated carriers

Alam, Parvez; Holst, Mikkel R.; Lauritsen, Line; Nielsen, Janni; Nielsen, Simone S. E.; Jensen, Poul Henning; Brewer, Jonathan R.; Otzen, Daniel E.; Nielsen, Mogens

doi:10.1186/s12987-022-00334-y

Cited by 17 publications

(16 citation statements)

References 54 publications

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“…This correlates well with dSTORM imaging by Aartsma and co-workers which showed that α-syn amyloid aggregates localize with endocytotic vesicles . It has also been shown that α-syn monomers colocalize with markers for late endosome/lysozyme Rab7 and the retromer protein VPS35 in brain endothelial cells after uptake from media . Furthermore, mitochondrial fragmentation has been observed in a PD disease mouse model with a heterozygous (D620N) mutation of Vacuolar Protein Sorting 35 (VPS35) .…”

Section: Resultssupporting

confidence: 85%

4-Oxo-2-nonenal-Induced α-Synuclein Oligomers Interact with Membranes in the Cell, Leading to Mitochondrial Fragmentation

et al. 2023

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Oxidative stress and formation of cytotoxic oligomers by the natively unfolded protein α-synuclein (α-syn) are both connected to the development of Parkinson's disease. This effect has been linked to lipid peroxidation and membrane disruption, but the specific mechanisms behind these phenomena remain unclear. To address this, we have prepared α-syn oligomers (αSOs) in vitro in the presence of the lipid peroxidation product 4-oxo-2-nonenal and investigated their interaction with live cells using in-cell NMR as well as stimulated emission depletion (STED) super-resolution and confocal microscopy. We find that the αSOs interact strongly with organellar components, leading to strong immobilization of the protein's otherwise flexible C-terminus. STED microscopy reveals that the oligomers localize to small circular structures inside the cell, while confocal microscopy shows mitochondrial fragmentation and association with both late endosome and retromer complex before the SOs interact with mitochondria. Our study provides direct evidence for close contact between cytotoxic α-syn aggregates and membraneous compartments in the cell.

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Section: Resultssupporting

confidence: 85%

4-Oxo-2-nonenal-Induced α-Synuclein Oligomers Interact with Membranes in the Cell, Leading to Mitochondrial Fragmentation

et al. 2023

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“…This has limited previous investigations and could potentially also explain the contradictory findings of the protein and lipid distributions in apicobasal cell polarity in general [ 9 , 11 , 42 ]. Here, we examined the apicobasal polarity of TfR in the established BBB model, which previously exhibited polarized alpha-synuclein transport [ 43 ], and has been reported to provide influx and efflux transport, depending on the specific compound [ 44 , 45 ]. To further validate the model, we examined the polarized transport of R123, a substrate for the transporter P-gp [ 35 , 46 ], and considered an efflux transporter in BECs [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells

Nielsen

Holst

Langthaler

et al. 2023

Fluids Barriers CNS

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The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma.

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“…Likewise, α-synuclein can cross the BBB in both directions, and α-synuclein can inhibit Aβ efflux in an LRP1-dependent manner (Sui et al, 2014). However, the polarized α-synuclein trafficking across BECs in the luminal-abluminal direction is directed by Rab7/VPS35 trafficking pathway, which is different from the Rab11-directed Aβ transcytosis in BECs (Alam et al, 2022). In addition, systemic inflammation promotes the α-synucleincontaining red blood cell (RBC)-derived extracellular vesicles (EVs) across BBB (Matsumoto et al, 2017).…”

Section: Dysregulation Of Bec Transportsmentioning

confidence: 98%

Blood–brain barrier endothelial cells in neurodegenerative diseases: Signals from the “barrier”

et al. 2023

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As blood–brain barrier (BBB) disruption emerges as a common problem in the early stages of neurodegenerative diseases, the crucial roles of barrier-type brain endothelial cells (BECs), the primary part of the BBB, have been reported in the pathophysiology of neurodegenerative diseases. The mechanisms of how early vascular dysfunction contributes to the progress of neurodegeneration are still unclear, and understanding BEC functions is a promising start. Our understanding of the BBB has gone through different stages, from a passive diffusion barrier to a mediator of central-peripheral interactions. BECs serve two seemingly paradoxical roles: as a barrier to protect the delicate brain from toxins and as an interface to constantly receive and release signals, thus maintaining and regulating the homeostasis of the brain. Most previous studies about neurodegenerative diseases focus on the loss of barrier functions, and far too little attention has been paid to the active regulations of BECs. In this review, we present the current evidence of BEC dysfunction in neurodegenerative diseases and explore how BEC signals participate in the pathogenesis of neurodegenerative diseases.

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Polarized α-synuclein trafficking and transcytosis across brain endothelial cells via Rab7-decorated carriers

Cited by 17 publications

References 54 publications

4-Oxo-2-nonenal-Induced α-Synuclein Oligomers Interact with Membranes in the Cell, Leading to Mitochondrial Fragmentation

4-Oxo-2-nonenal-Induced α-Synuclein Oligomers Interact with Membranes in the Cell, Leading to Mitochondrial Fragmentation

Apicobasal transferrin receptor localization and trafficking in brain capillary endothelial cells

Blood–brain barrier endothelial cells in neurodegenerative diseases: Signals from the “barrier”

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