Imaging Protein Misfolding in the Brain Using β-Sheet Ligands

Harada, Ryuichi; Okamura, Nobuyuki; Furumoto, Shozo; Yanai, Kazuhiko

doi:10.3389/fnins.2018.00585

Cited by 31 publications

(21 citation statements)

References 103 publications

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“…As GSK3β has been shown to play a positive factor in the UPR of injured livers [ 31 ], we examined proteostatic stress by detecting the aggregated protein as stained by thioflavin T (ThT), which serves as a ligand for imaging protein aggregates expressing cross-β sheet structure [ 33 ]. As shown in Figure 4 A, the MCD diet induced an increase in the ThT signal in the liver of the WT group, whereas MCD had no impact on that of the miR-29a group.…”

Section: Resultsmentioning

confidence: 99%

miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

Yang

Wang

et al. 2020

IJMS

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MicroRNA-29a (miR-29a) has been shown to ameliorate hepatocellular damage, such as in the context of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and cholestatic injury. However, the mechanism mediating the hepatoprotective effect of miR-29a in diet-induced NASH remains elusive. In the present study, C57BL/6 mice of wild-type (WT) or miR-29a overexpression were fed with methionine–choline sufficient (MCS) or methionine–choline-deficient (MCD) diet for four weeks. The C57BL/6 mice harboring miR-29a overexpression presented reduced plasma AST, hepatic CD36, steatosis, and fibrosis induced by MCD. The TargetScan Release7.2-based bioinformatic analysis, KEGG pathway analysis, and luciferase reporter assay confirmed that miR-29a targets 3′UTR of glycogen synthase kinase 3 beta (Gsk3b) mRNA in the HepG2 hepatocyte cell line. Furthermore, miR-29a overexpression in the MCD-fed group resulted in inhibition of Gsk3b mRNA and GSK3β protein levels in the liver. GSK3β was notably expressed jointly with the extent of aggregated protein, which was then identified to be associated with mitochondrial unfolded protein response (UPRmt), but not with endoplasmic reticulum UPR (UPRER). Additionally, in silico analysis of protein–protein interaction, in vivo, and in vitro correlation analyses of protein expression demonstrated that GSK3β closely associated with sirtuin 1(SIRT1). Finally, the implication of SIRT1-mediated mitochondrial biogenesis in the perturbation of proteostasis was observed. We herein provide novel insight into a hepatoprotective pathway, whereby miR-29a inhibits GSK3β to repress SIRT1-mediated mitochondrial biogenesis, leading to alleviation of mitochondrial proteostatic stress and UPRmt in the context of NASH. miR-29a, GSK3β, and SIRT1 could thus serve as possible therapeutic targets to improve the treatment of NAFLD/NASH.

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Section: Resultsmentioning

confidence: 99%

miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

Yang

Wang

et al. 2020

IJMS

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“…For evaluation of each of the tracers, we first tested our docking strategy on Tau PiD using the structural information on Tau PiD from the Protein Data Bank (PDB ID: 6GX5) [ 8 ]. PET tracers are designed to bind to cross-β structure [ 29 ]; therefore, we assumed that PET tracers bind to the C-terminal core region of tau filaments and not to the other flexible region [ 4 , 8 ]. The docking results show that a number of surface binding sites (S1–S11 in Figure 1 B) in Tau PiD can potentially bind PET probes.…”

Section: Resultsmentioning

confidence: 99%

Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

Mishra

Yamaguchi

Higuchi

et al. 2020

IJMS

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In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.

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“…The identification of lead compounds for the imaging of Aβ proteinopathies has been relatively easier since most β-sheet binding ligands have a high affinity for Aβ fibrils, with which NFTs coexist in AD and both are colocalized in the gray matter structures [42,152]. In spite of controversy surrounding the subject, PHFs predominantly found in NFTs in in vitro experiments suggest a β-sheet structured core similar to that characteristic of Aβ and α-syn fibrillar aggregates [42].…”

Section: Pet-tracers For the Imaging Of Tau Aggregatesmentioning

confidence: 99%

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

2020

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Ironically, population aging which is considered a public health success has been accompanied by a myriad of new health challenges, which include neurodegenerative disorders (NDDs), the incidence of which increases proportionally to age. Among them, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common, with the misfolding and the aggregation of proteins being common and causal in the pathogenesis of both diseases. AD is characterized by the presence of hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFTs), and senile plaques the main component of which is β-amyloid peptide aggregates (Aβ). The neuropathological hallmark of PD is α-synuclein aggregates (α-syn), which are present as insoluble fibrils, the primary structural component of Lewy body (LB) and neurites (LN). An increasing number of non-invasive PET examinations have been used for AD, to monitor the pathological progress (hallmarks) of disease. Notwithstanding, still the need for the development of novel detection tools for other proteinopathies still remains. This review, although not exhaustively, looks at the timeline of the development of existing tracers used in the imaging of Aβ and important moments that led to the development of these tracers.

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Imaging Protein Misfolding in the Brain Using β-Sheet Ligands

Cited by 31 publications

References 103 publications

miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis

Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

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