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

van der Wel, Patrick C.A.

doi:10.1042/bst20230731

Cited by 3 publications

(1 citation statement)

References 95 publications

(172 reference statements)

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“…A kinetically competing, N17-independent aggregation pathway also exists for Huntingtin exon 1 which resembles that of simple polyglutamine and dominates upon disruption of N17 association or its partial excision (Jayaraman et al 2012b). Notably, solid-state NMR experiments concluded that the core of Httex1 fibrils was structurally similar to simple polyglutamine fragments, comprising of an inter-digitating hydrogen bond network formed between adjacent layers of polyQ β-hairpins through glutamine sidechains while the flanking N17 remains helical (Sivanandam et al 2011; Hoop et al 2016; van der Wel 2024).…”

Section: Introductionmentioning

confidence: 99%

Transient interdomain interactions modulate the monomeric structural ensemble and oligomerization landscape of Huntingtin Exon 1

Mohanty,

Phan,

Mittal

2024

Preprint

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Polyglutamine expansion (≥ 36 residues) within the N-terminal exon-1 of Huntingtin (Httex1) leads to Huntington's disease, a neurogenerative condition marked by the presence of intranuclear Htt inclusions. Notably, the polyglutamine tract in Httex1 is flanked by an N-terminal coiled-coil domain - N17 (17 amino acids), which undergoes self-association to promote the formation of soluble Httex1 oligomers and brings the aggregation-prone polyQ tracts in close spatial proximity. However, the mechanisms underlying the subsequent conversion of soluble oligomers into insoluble β-rich aggregates with increasing polyQ length, remain unclear. Current knowledge suggests that expansion of the polyQ tract increases its helicity, and this favors its oligomerization and aggregation. In addition, studies utilizing conformation-specific antibodies and a stable coiled-coil heterotetrametric system fused to polyQ indicate that domain cross-talk (i.e., interdomain interactions) may be necessary to efficiently promote the emergence of toxic conformations (in monomers and oligomers) and fibrillar aggregation. Here, we performed extensive atomistic molecular dynamics (MD) simulations (aggregate time ~ 0.7 ms) of N17-polyQ fragments to uncover the interplay between structural transformation and domain cross-talk on the monomeric structural ensemble and oligomerization landscape of Httex1. Our simulation ensembles of N17-polyQ monomers validated against 13C NMR chemical shifts indicated that in addition to elevated α-helicity, polyQ expansion also favors transient, interdomain (N17-polyQ) interactions which result in the emergence of β-conformations. Further, interdomain interactions decreased the overall stability of N17-mediated dimers by counteracting the stabilizing effect of increased α-helicity and promoted a heterogenous oligomerization landscape on the sub-microsecond timescale. Overall, our study uncovers the significance of domain cross-talk in modulating the monomeric conformational ensemble and oligomerization landscape of Httex1 to favor the formation of amyloid aggregates.

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Section: Introductionmentioning

confidence: 99%

Transient interdomain interactions modulate the monomeric structural ensemble and oligomerization landscape of Huntingtin Exon 1

Mohanty,

Phan,

Mittal

2024

Preprint

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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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Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington’s disease

Helabad¹,

Matlahov²,

Daldrop³

et al. 2023

Preprint

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Neurodegeneration in Huntington's disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HttEx1) fragment, whose polyglutamine (polyQ) segment is expanded. Unlike amyloid fibrils from Parkinson's and Alzheimer's diseases, the atomic-level structure of HttEx1 fibrils has remained unknown, limiting diagnostic and treatment efforts. We present and analyze the structure of fibrils formed by polyQ peptides and polyQ-expanded HttEx1. Atomic-resolution perspectives are enabled by an integrative analysis and unrestrained all-atom molecular dynamics (MD) simulations incorporating experimental data from electron microscopy (EM), solid-state NMR, and other techniques. Visualizing the HttEx1 subdomains in atomic detail helps explaining the biological properties of these protein aggregates, as well as paves the way for targeting them for detection and degradation.

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

Cited by 3 publications

References 95 publications

Transient interdomain interactions modulate the monomeric structural ensemble and oligomerization landscape of Huntingtin Exon 1

Transient interdomain interactions modulate the monomeric structural ensemble and oligomerization landscape of Huntingtin Exon 1

Inhibitor-based modulation of huntingtin aggregation mechanisms reduces fibril toxicity

Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington’s disease

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