Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism

Cooper, Joanna M.; Lathuilière, Aurélien; Migliorini, Mary; Arai, Allison L.; Wani, Mashhood; Dujardin, Simon; Muratoglu, Selen C.; Hyman, Bradley T.; Strickland, Dudley K.

doi:10.1016/j.jbc.2021.100715

Cited by 56 publications

(46 citation statements)

References 84 publications

(96 reference statements)

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“…We believe that our findings will facilitate understanding of other LDLR family interactions associated with pathogenesis 27,28,30,31 and improving respective therapeutics and disease treatments. Regarding hemophilia A, our results suggest that development of a longer‐acting therapeutical FVIII may be based on shielding of its large LRP1‐binding site via a fusion of a thrombin‐cleavable protein, allowing FVIII activation during blood coagulation.…”

Section: Discussionmentioning

confidence: 82%

“…In FVIII clearance, LRP1 acts in concert with the hepatic low density lipoprotein receptor (LDLR) 5 . Both belong to the LDLR family of endocytic receptors 23–26 associated with many processes with clinical significance 27–31 . Other members of the LDLR family, very low density lipoprotein receptor (vLDLR) and megalin, can also interact with FVIII with unknown functional relevance 32,33 …”

Section: Introductionmentioning

confidence: 99%

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Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Chun

Kurasawa

Olivares

et al. 2022

Journal of Thrombosis and Haemostasis

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Background Deficiency in blood coagulation factor VIII (FVIII) results in life‐threating bleeding (hemophilia A) treated by infusions of FVIII concentrates. To improve disease treatment, FVIII has been modified to increase its plasma half‐life, which requires understanding mechanisms of FVIII catabolism. An important catabolic actor is hepatic low density lipoprotein receptor‐related protein 1 (LRP1), which also regulates many other clinically significant processes. Previous studies showed complexity of FVIII site for binding LRP1. Objectives To characterize binding sites between FVIII and LRP1 and suggest a model of the interaction. Methods A series of recombinant ligand‐binding complement‐type repeat (CR) fragments of LRP1 including mutated variants was generated in a baculovirus system and tested for FVIII interaction using surface plasmon resonance, tissue culture model, hydrogen–deuterium exchange mass spectrometry, and in silico. Results Multiple CR doublets within LRP1 clusters II and IV were identified as alternative FVIII‐binding sites. These interactions follow the canonical binding mode providing major binding energy, and additional weak interactions are contributed by adjacent CR domains. A representative CR doublet was shown to have multiple contact sites on FVIII. Conclusions FVIII and LRP1 interact via formation of multiple complex contacts involving both canonical and non‐canonical binding combinations. We propose that FVIII‐LRP1 interaction occurs via switching such alternative binding combinations in a dynamic mode, and that this mechanism is relevant to other ligand interactions of the low‐density lipoprotein receptor family members including LRP1.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Chun

Kurasawa

Olivares

et al. 2022

Journal of Thrombosis and Haemostasis

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“…The knockdown of LRP1 also suppressed the spreading of tau in the brain of mice expressing human tau P301L mutant. Cooper et al (2021) also demonstrated LRP1-mediated internalization of tau aggregates extracted from AD patients. In their study, internalized tau monomers were degraded in lysosomes, but internalized tau aggregates induced tau seeding in the recipient cells.…”

Section: Molecular Mechanisms Of Extracellular Tau Uptakementioning

confidence: 86%

“…In their study, internalized tau monomers were degraded in lysosomes, but internalized tau aggregates induced tau seeding in the recipient cells. A member of the LDL-receptor superfamily, SORLA, was also identified as a receptor of extracellular tau ( Cooper et al, 2021 ). mAChRs are also known to mediate clathrin-mediated internalization of tau.…”

Section: Molecular Mechanisms Of Extracellular Tau Uptakementioning

confidence: 99%

The Fate of Tau Aggregates Between Clearance and Transmission

Seitkazina

Kim

Fagan

et al. 2022

Front. Aging Neurosci.

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Neuronal accumulation of mis-folded tau is the pathological hallmark of multiple neurodegenerative disorders, including Alzheimer’s disease. Distinct from amyloid plaques, which appear simultaneously throughout the brain, tau pathology develops first in a specific brain region and then propagates to neuroanatomically connected brain regions, exacerbating the disease. Due to the implication in disease progression, prevention of tau transmission is recognized as an important therapeutic strategy that can halt disease progression in the brain. Recently, accumulating studies have demonstrated diverse cellular mechanisms associated with cell-to-cell transmission of tau. Once transmitted, mis-folded tau species act as a prion-like seed for native tau aggregation in the recipient neuron. In this review, we summarize the diverse cellular mechanisms associated with the secretion and uptake of tau, and highlight tau-trafficking receptors, which mediate tau clearance or cell-to-cell tau transmission.

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“…[47] Recent research has identified LRP1 as an endocytic receptor for Tau uptake. [108,129] Interestingly, while LRP1 was shown to efficiently bind and internalize monomeric Tau for lysosomal degradation, it promoted seeding of endogenous Tau aggregation by uptake of pathological Tau forms. [129] Stabilization of Tau seeds by Clusterin may conceivably exacerbate this effect.…”

Section: Role Of Clusterin In Aggregate Clearancementioning

confidence: 99%

The chaperone Clusterin in neurodegeneration−friend or foe?

Yuste-Checa

Bracher

2022

BioEssays

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Fibrillar protein aggregates are the pathological hallmark of a group of age-dependent neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Aggregates of the microtubule-associated protein Tau are observed in Alzheimer's disease and primary tauopathies. Tau pathology propagates from cell to cell in a prion-like process that is likely subject to modulation by extracellular chaperones such as Clusterin. We recently reported that Clusterin delayed Tau fibril formation but enhanced the activity of Tau oligomers to seed aggregation of endogenous Tau in a cellular model. In contrast, Clusterin inhibited the propagation of α-Synuclein aggregates associated with Parkinson's disease. These findings raise the possibility of a mechanistic link between Clusterin upregulation observed in Alzheimer's disease and the progression of Tau pathology. Here we review the diverse functions of Clusterin in the pathogenesis of neurodegenerative diseases, focusing on evidence that Clusterin may act either as a suppressor or enhancer of pathology.

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Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism

Cited by 56 publications

References 84 publications

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

The Fate of Tau Aggregates Between Clearance and Transmission

The chaperone Clusterin in neurodegeneration−friend or foe?

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