Clusterin in Alzheimer's disease: An amyloidogenic inhibitor of amyloid formation?

Spatharas, Panagiotis M.; Nasi, Georgia I.; Tsiolaki, Paraskevi L.; Theodoropoulou, Marilena K.; Παπανδρεου, Νικολαοσ; Hoenger, Andreas; Trougakos, Ioannis P.; Iconomidou, Vassiliki A.

doi:10.1016/j.bbadis.2022.166384

Cited by 17 publications

(11 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, CLU protein was highly expressed in CZS phenotypes compared to CTR. This could be a result of the upsurge in SNCA and TTR concentrations, possibly to mitigate the protein aggregation process. , Furthermore, there are reports proving that ZIKV infection accelerates Alzheimer’s disease phenotypes, providing additional context to the potential long-term consequences of ZIKV infection. From this perspective, other amyloidosis outcomes such as Parkinson’s disease associated with ZIKV infection could not be discarded.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome

Sosa-Acosta,

Quiñones-Vega,

Guedes

et al. 2024

J. Proteome Res.

View full text Add to dashboard Cite

The Zika virus (ZIKV) can be vertically transmitted, causing congenital Zika syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances of developing CZS. This syndrome involves several pathologies with a complex diagnosis. In this work, we aim to identify biological processes and molecular pathways related to CZS and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. We analyzed serum samples of healthy pregnant women and ZIKV-infected pregnant women bearing nonmicrocephalic and microcephalic fetuses. A total of 1090 proteins and 512 metabolites were identified by bottom-up proteomics and untargeted metabolomics, respectively. Univariate and multivariate statistical approaches were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as CZS signatures. Five proteins and four metabolites were selected as CZS biomarker candidates. Serum multiomics analysis led us to propose nine putative biomarkers for CZS prognosis with high sensitivity and specificity.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome

Sosa-Acosta,

Quiñones-Vega,

Guedes

et al. 2024

J. Proteome Res.

View full text Add to dashboard Cite

show abstract

“…When the modified and wild-type proteins were fused, a much more potent inhibitor was obtained. A completely different aggregation-prone protein can also act as an inhibitor; for example, the mouse prion protein [ 190 ] or the molecular chaperone clusterin [ 191 ] binds to the ends of growing fibrils of beta-amyloid, inhibiting their elongation.…”

Section: Effect Of Inhibitor Binding On Amyloid Fibril Formationmentioning

confidence: 99%

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

Sedov

Khaibrakhmanova

2022

IJMS

View full text Add to dashboard Cite

Inhibition of fibril formation is considered a possible treatment strategy for amyloid-related diseases. Understanding the molecular nature of inhibitor action is crucial for the design of drug candidates. In the present review, we describe the common kinetic models of fibril formation and classify known inhibitors by the mechanism of their interactions with the aggregating protein and its oligomers. This mechanism determines the step or steps of the aggregation process that become inhibited and the observed changes in kinetics and equilibrium of fibril formation. The results of numerous studies indicate that possible approaches to antiamyloid inhibitor discovery include the search for the strong binders of protein monomers, cappers blocking the ends of the growing fibril, or the species absorbing on the surface of oligomers preventing nucleation. Strongly binding inhibitors stabilizing the native state can be promising for the structured proteins while designing the drug candidates targeting disordered proteins is challenging.

show abstract

“…In the context of its known biochemical properties, this expression pattern has suggested that localized synthesis of CLU serves to protect a variety of secretory, mucosal, and other barrier cells from damaging stress [ 30 ]. In recent years, evidence has accumulated to suggest the use of CLU to treat various disorders, including Alzheimer’s disease [ 31 , 32 ], cardiovascular disease [ 33 , 34 ], osteoarthritis [ 35 ] and diseases of the eye [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy

Chintala

Pan

Satapathy

et al. 2023

IJMS

View full text Add to dashboard Cite

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

show abstract

Clusterin in Alzheimer's disease: An amyloidogenic inhibitor of amyloid formation?

Cited by 17 publications

References 84 publications

Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome

Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy

Contact Info

Product

Resources

About