A new era for understanding amyloid structures and disease

Iadanza, M.G.; Jackson, Matthew P.; Hewitt, Eric W.; Ranson, Neil A.; Radford, Sheena E.

doi:10.1038/s41580-018-0060-8

Cited by 766 publications

(746 citation statements)

References 291 publications

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“…Amyloid aggregates are signatures of various neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, and small soluble oligomeric intermediates formed during amyloid fibrillation are typically associated with cytotoxicity [24, 25]. Although many amyloid aggregates share a common cross- β sheet structural motif that is an assembly of identical copies of amyloid peptides, oligomers and fibrils are highly heterogeneous in terms of their structure and size [26, 27]. Interestingly, not all aggregation intermediates are equally toxic [28].…”

Section: Resolving Structural Heterogeneities Within Amyloid Fibersmentioning

confidence: 99%

Single-molecule orientation localization microscopy for resolving structural heterogeneities between amyloid fibrils

Ding

Mazidi

et al. 2020

Preprint

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5Simultaneous measurements of single-molecule positions and orientations provide critical insight 6 into a variety of biological and chemical processes. Various engineered point spread functions (PSFs) 7 have been introduced for measuring the orientation and rotational diffusion of dipole-like emitters, 8 but the widely used Cramér-Rao bound only evaluates performance for one specific orientation at 9 a time. Here, we report a performance metric, termed variance upper bound (VUB), that yields 10 a global maximum CRB for all possible molecular orientations, thereby enabling the measurement 11 performance of any PSF to be computed efficiently (~1000 times faster than calculating average 12 CRB). Our VUB reveals that the simple polarized standard PSF provides robust and precise ori-13 entation measurements if emitters are near a refractive index interface. Using the polarized PSF, 14 we measure the orientations and positions of Nile red (NR) molecules transiently bound to amy-15 loid aggregates. Our super-resolved images reveal the main binding mode of NR to amyloid fibers, 16 as well as structural heterogeneities within amyloid fibrillar networks, that cannot be resolved by 17 single-molecule localization alone. 19A key strength of single-molecule localization mi-20 croscopy (SMLM) is its ability to measure the full distri-21 bution of the phenomena under study and avoid ensemble 22 averaging. Going beyond standard SMLM to measure 23 SM position and orientation simultaneously is critical 24 for understanding a variety of nanoscale biological and 25 chemical processes, such as the motions of molecular mo-26 tors [1-3], the complex higher-order structures of DNA 27 [4, 5], and reaction kinetics within catalytic nanoparti-28 cles [6]. To perform these measurements, molecular po-29 sition and orientation must be encoded within the shape 30 of the image produced by a microscope, i.e., its point-31 spread function (PSF). However, balancing the need to 32 resolve various orientations unambiguously with the need 33 to detect SMs efficiently with high signal-to-background 34 ratio (SBR) remains a challenge that limits the adoption 35 of Single-Molecule Orientation Localization Microscopy 36 (SMOLM) for biological and chemical applications; exist-37 ing techniques either cannot discriminate between similar 38 types of molecular motions or cannot detect weak fluo-39 rescent emitters. 40 In order to design a PSF for measuring molecular ori-41 entation, one must have a figure of merit for compari-42 son. The Cramér-Rao bound (CRB), which is the best-43 possible precision achievable by an unbiased estimator, 44 has been used extensively for evaluating [7] and opti-45 mizing [8, 9] SMLM techniques. However, since CRB 46 quantifies measurement performance locally, in the sense 47 65 tection channels, exhibiting a polarized (standard) PSF, 66 provides superior measurement precision when molecules 67 are near a refractive index interface, especially when they 68 lie perpendicular to the optical axis, even under low SBR. 69 ...

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Section: Resolving Structural Heterogeneities Within Amyloid Fibersmentioning

confidence: 99%

Single-molecule orientation localization microscopy for resolving structural heterogeneities between amyloid fibrils

Ding

Mazidi

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…44 However, the predicted structure of BBF2H7 does not contain β-sheet structures. 49 In this study, we found that BSP fragments also exhibit high aggregation propensity and form fibrils. 45 The β-sheet form of α-synuclein shows higher aggregation propensity than those of random-coil form.…”

Section: Discussionmentioning

confidence: 64%

Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis

et al. 2019

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractIntramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site-1 protease (S1P) and site-2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7-derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid β (Aβ) protein. These results advance the understanding of poorly characterized ER stress-dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders. |MATSUHISA eT Al.

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“…There is controversy about which forms of proteins are toxic in neurodegenerative disorders. While some studies attribute toxicity to the aggregated form, other studies suggest aggregation to be a beneficial process that protects the cell from intermediate or misfolded toxic proteins [138,139]. Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are also discussed as potential prion-like diseases for which misfolded proteins are known to propagate and convert other proteins into pathological forms [140,141].…”

Section: Targeted Proteolysis Via Lysosomes or The Ermentioning

confidence: 99%

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

et al. 2020

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To interfere with cell function, many scientists rely on methods that target DNA or RNA due to the ease with which they can be applied. Proteins are usually the final executors of function but are targeted only indirectly by these methods. Recent advances in targeted degradation of proteins based on proteolysis-targeting chimaeras (PROTACs), ubiquibodies, deGradFP (degrade Green Fluorescent Protein) and other approaches have demonstrated the potential of interfering directly at the protein level for research and therapy. Proteins can be targeted directly and very specifically by antibodies, but using antibodies inside cells has so far been considered to be challenging. However, it is possible to deliver antibodies or other proteins into the cytosol using standard laboratory equipment. Physical methods such as electroporation have been demonstrated to be efficient and validated thoroughly over time. The expression of intracellular antibodies (intrabodies) inside cells is another way to interfere with intracellular targets at the protein level. Methodological strategies to target the inside of cells with antibodies, including delivered antibodies and expressed antibodies, as well as applications in the research areas of neurobiology, viral infections and oncology, are reviewed here. Antibodies have already been used to interfere with a wide range of intracellular targets. Disease-related targets included proteins associated with neurodegenerative diseases such as Parkinson's disease (α-synuclein), Alzheimer's disease (amyloid-β) or Huntington's disease (mutant huntingtin [mHtt]). The applications of intrabodies in the context of viral infections include targeting proteins associated with HIV (e.g. HIV1-TAT, Rev, Vif, gp41, gp120, gp160) and different oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-Barr virus, and they have been used to interfere with various targets related to different processes in cancer, including oncogenic pathways, proliferation, cell cycle, apoptosis, metastasis, angiogenesis or neo-antigens (e.g. p53, human epidermal growth factor receptor-2 [HER2], signal transducer and activator of transcription 3 [STAT3], RAS-related RHO-GTPase B (RHOB), cortactin, vascular endothelial growth factor receptor 2 [VEGFR2], Ras, Bcr-Abl). Interfering at the protein level allows questions to be addressed that may remain unanswered using alternative methods. This review addresses why direct targeting of proteins allows unique insights, what is currently feasible in vitro, and how this relates to potential therapeutic applications.Therapeutic antibodies are valuable drugs, which mostly act outside of cells.Reaching the numerous drug targets that reside inside cells by antibodies is possible in vitro and allows unique insights compared with other methods.Applying antibodies inside cells for therapeutic purposes has been explored in animal models and promises specific therapeutic benefits in neurobiology, virology and oncology.

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A new era for understanding amyloid structures and disease

Cited by 766 publications

References 291 publications

Single-molecule orientation localization microscopy for resolving structural heterogeneities between amyloid fibrils

Single-molecule orientation localization microscopy for resolving structural heterogeneities between amyloid fibrils

Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

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