Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils

Matlahov, Irina; Boatz, Jennifer C.; Wel, Patrick C.A. van der

doi:10.1016/j.yjsbx.2022.100077

Cited by 6 publications

(6 citation statements)

References 78 publications

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“…On the contrary, HttEx1Q44 fibrils formed larger clusters of fibrils ( Fig. 4F ) (Boatz et al, 2020; Isas et al, 2021; Matlahov et al, 2022; Nazarov et al, 2022). We noted a large variation between the sizes of these clusters: from just a few fibrils of 50-100 nm to enormous clusters of several µm in width.…”

Section: Resultsmentioning

confidence: 96%

“…Tracers for other aggregating proteins are also in development. For Huntingtin, the protein that aggregates in HD, tracers have passed tests on ex vivo samples (Delva et al, 2022; Herrmann et al, 2021; Liu et al, 2021; Liu et al, 2020; Matlahov et al, 2022). Even though PET tracers remain a valuable tool in diagnosis and in monitoring neurogenerative diseases directly in the brain, they present some limitations such as costs and limited accessibility (Ossenkoppele & Hansson, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Fibril Paint to detect Amyloids and determine Fibril Length

Aragonès Pedrola,

Dekker,

Garfagnini

et al. 2023

Preprint

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Protein aggregation is related to the development of amyloid diseases, such as Alzheimer’s Disease and Huntington’s Disease. It is of great importance to detect aggregates at the earliest stage possible, which is a prerequisite for early diagnosis. Here, we present a method to monitor protein fibril size from early aggregation steps. We designed a peptide, FibrilPaint1, that specifically recognises and fluorescently labels various fibrils from diseases, but not their monomeric precursors. In combination with Flow Induced Dispersion Analysis, a microfluidics technology, we determined the molecular size of amyloid fibrils with sub-microliter sample volumes. FibrilPaint1 specifically detects structurally unrelated fibrils from Huntingtin and Tau, includingex vivosamples derived from Alzheimer’s Disease, Frontotemporal Dementia and Corticobasal Degeneration patients. The ability to recognise multiple amyloids but not monomeric precursors makes FibrilPaint1 a novel tool for diagnostic applications for amyloid diseases.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Fibril Paint to detect Amyloids and determine Fibril Length

Aragonès Pedrola,

Dekker,

Garfagnini

et al. 2023

Preprint

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“…surface residues challenging. A recent study [ 34 ] deployed specialized ssNMR spectral editing techniques to selectively detect glutamines on the fibril surface, even against a larger background of residues in the fibril core. This was based on an approach designed to detect residues experiencing intermediate motion, by suppressing signals from the most rigid (core) residues that normally dominate (cross-polarization) ssNMR spectra.…”

Section: Ssnmr Of Polyq Amyloid Coresmentioning

confidence: 99%

Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

van der Wel

2024

Biochemical Society Transactions

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The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have seen much progress in our understanding of these misfolded protein inclusions, thanks to advances in techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders have presented special challenges to structural elucidation. This review discusses the special role of ssNMR analysis in the study of protein aggregates associated with CAG repeat expansion disorders. In these diseases, the misfolding and aggregation affect mutant proteins with expanded polyglutamine segments. The most common disorder, Huntington's disease (HD), is connected to the mutation of the huntingtin protein. Since the discovery of the genetic causes for HD in the 1990s, steady progress in our understanding of the role of protein aggregation has depended on the integrative and interdisciplinary use of multiple types of structural techniques. The heterogeneous and dynamic features of polyQ protein fibrils, and in particular those formed by huntingtin N-terminal fragments, have made these aggregates into challenging targets for structural analysis. ssNMR has offered unique insights into many aspects of these amyloid-like aggregates. These include the atomic-level structure of the polyglutamine core, but also measurements of dynamics and solvent accessibility of the non-core flanking domains of these fibrils' fuzzy coats. The obtained structural insights shed new light on pathogenic mechanisms behind this and other protein misfolding diseases.

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“…Here, the ssNMR data are of particular value, as they provide a direct perspective on the fibril surface (10,12,55). Dynamic flanking segments decorate the fibril surface and are implicated in protein-protein interactions and protein-lipid interactions (56,57).…”

Section: Modulation Of Toxicitymentioning

confidence: 99%

Inhibitor-based modulation of huntingtin aggregation mechanisms reduces fibril toxicity

Jain

Trombetta-Lima

Matlahov

et al. 2023

Preprint

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Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) segment in the exon 1 of the huntingtin (HttEx1) protein. This polyQ expansion leads to protein misfolding and the formation of β-sheet-rich fibrillar aggregates. Several studies have shown that these protein deposits can cause cytotoxicity, suggesting the development of small molecule aggregation inhibitors as potential modulators of HD pathogenesis. This requires a molecular understanding of the impacts of such modulators on the interplay of aggregation, polymorphism and toxic gain-of-function. Here, we study how a polyphenol modulates the HttEx1 aggregation mechanism at sub-stoichiometric ratios. Moreover, we examine how the disrupted aggregation process impacts the protein's misfolded structure and neurotoxic properties. We combine measurements of aggregation kinetics, electron microscopy, solid-state NMR, cytometry, and cytotoxicity assays. A notable delay of protein aggregation was observed even at sub-stoichiometric ratios of curcumin relative to the HttEx1 protein. Mechanistically, extension of the lag phase indicates an impact on the primary nucleation process that underpins the complex HttEx1 aggregation pathway, with an apparent role for β-hairpin formation. Remarkably, the deposits formed (more slowly) in presence of inhibitor displayed reduced toxicity in cultured neuronal cells, seemingly derived from their modulated structures. Thus, curcumin has a multifaceted effect based on delaying the fibril formation, while also changing the toxic properties of formed fibrils. Our findings highlight the ability of small molecule inhibitors to modulate the protein misfolding landscape, with potential implications for treatment strategies in HD and other protein deposition disorders.

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Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils

Cited by 6 publications

References 78 publications

Fibril Paint to detect Amyloids and determine Fibril Length

Fibril Paint to detect Amyloids and determine Fibril Length

Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

Inhibitor-based modulation of huntingtin aggregation mechanisms reduces fibril toxicity

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