Cross β-Sheet Conformation of Keratin 8 Is a Specific Feature of Mallory–Denk Bodies Compared With Other Hepatocyte Inclusions

Mahajan, Vineet; Klingstedt, Therése; Simon, Rozalyn; Nilsson, K. Peter R.; Thueringer, Andrea; Kashofer, Karl; Haybaeck, Johannes; Denk, Helmut; Abuja, Peter M.; Zatloukal, Kurt

doi:10.1053/j.gastro.2011.05.039

Cited by 44 publications

(57 citation statements)

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“…MDBs consist of keratin 8 and keratin 18, and earlier experiments have revealed keratin 8 to be more prone to form aggregates [43]. This result was confirmed with h-HTAA staining of transfected cells, which showed that keratin 8 spontaneously acquired a cross-β-sheet structure, whereas keratin 18 inclusions positive for h-HTAA only were found after the cells were exposed to oxidative stress [44]. These results clearly show that LCOs can be applied to study intracellular protein aggregates, a property that is highly valued since several studies indicate that the formation of amyloid in many cases is initiated inside the cell [45,46].…”

Section: The Study Of Intracellular Protein Aggregatessupporting

confidence: 67%

“…Recently, p-FTAA and the heptameric (h-) LCO h-HTAA were shown to specifically label misfolded keratin forming MDBs in transfected cells, a mouse model and human liver tissue. Other types of hepatic protein inclusions containing p62 and ubiquitin, but not keratin, remained unstained with h-HTAA, indicating that keratin was the protein displaying the cross-β-sheet structure recognized by the LCOs [44]. MDBs consist of keratin 8 and keratin 18, and earlier experiments have revealed keratin 8 to be more prone to form aggregates [43].…”

Section: The Study Of Intracellular Protein Aggregatesmentioning

confidence: 89%

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Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates

Klingstedt

Nilsson

2012

Biochemical Society Transactions

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The deposition of protein aggregates in various parts of our body gives rise to several devastating diseases, and the development of probes for the selective detection of aggregated proteins is crucial to advance our understanding of the pathogenesis underlying these diseases. LCPs (luminescent conjugated polythiophenes) are fluorescent probes that bind selectively to protein aggregates. The conjugated thiophene backbone is flexible and offers a connection between the conformation and the emission properties, hence binding of LCPs gives the molecule a spectral fingerprint. The present review covers the utilization of LCPs to study the heterogeneity of protein aggregates. It emphasizes specifically the introduction of well-defined probes called LCOs (luminescent conjugated oligothiophenes) and reports how these molecules can be used for real-time in vivo imaging of cerebral plaques as well as for spectral discrimination of protein aggregates and detection of early species in the fibrillation pathway of amyloid β-peptide.

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Section: The Study Of Intracellular Protein Aggregatessupporting

confidence: 67%

Section: The Study Of Intracellular Protein Aggregatesmentioning

confidence: 89%

Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates

Klingstedt

Nilsson

2012

Biochemical Society Transactions

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“…Especially as LCOs and LCPs have proven useful for detection of pathological protein aggregates that go undetected by conventional ligands such as ThT and CR. 23,26,29–34 However, such a study must include extensive fibrillation experiments of Aβ performed under different conditions and also include different variants of the Aβ peptide as it was recently shown that Japanese mutant Aβ rapidly formed amyloid fibrils that were only weakly stained by ThT. 49 So far we can only speculate about the nature of the LCO positive protein assemblies preceding amyloid fibril formation.…”

Section: Resultsmentioning

confidence: 99%

“…28 LCPs and LCOs have been utilized for staining of thioflavinophilic and congophilic protein aggregates associated with a variety of diseases 21–26 and also for identifying disease associated protein aggregates that goes undetected with ThT and CR. 23,26,29–34 For instance, LCPs and LCOs have proven very useful for identification of protein aggregates associated with distinct prion strains 26,29,31 and for staining of intracelllular inclusion bodies 34 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates

et al. 2011

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Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting: i) early non-thioflavinophilic protein assemblies of Aβ1-42 and insulin preceding the formation of amyloid fibrils and ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimer’s diease brain tissue (Aβ plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases.

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“…In this study, we found out that cross b-sheet conformation of MDBs depends on oxidative stress and K8 but not on p62. 38 Luminescent-conjugated oligothiophenes (LCOs), h-HTAA and p-FTAA are fluorescent amyloid ligands specifically binding proteins with cross b-sheet conformation. We used LCOs to investigate conformational changes in MDBs in situ in human and murine livers as well as in transfection studies.…”

Section: Discussionmentioning

confidence: 99%

Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

Haybaeck

Stumptner

Thueringer

et al. 2012

Laboratory Investigation

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Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8À/À and krt18 À/À mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8 À/À and krt18 À/À compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18 À/À mice already at an early stage of intoxication in contrast to krt8 À/À mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8 À/À , krt18 À/À and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18 À/À and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8 À/À mice, steatosis was less, ballooning, and MDBs were absent. krt18 À/À mice developed MDBs whereas krt8 À/À mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8À/À and krt18 À/À mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8 À/À and krt18 À/À mice on different genetic backgrounds were investigated.

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Cross β-Sheet Conformation of Keratin 8 Is a Specific Feature of Mallory–Denk Bodies Compared With Other Hepatocyte Inclusions

Cited by 44 publications

References 36 publications

Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates

Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates

Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates

Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

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