Prion-like properties of the mutant huntingtin protein in living organisms: the evidence and the relevance

Alpaugh, Melanie; Denis, Hélèna L.; Cicchetti, Francesca

doi:10.1038/s41380-021-01350-4

Cited by 10 publications

(5 citation statements)

References 103 publications

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“…The mutated htt forms were shown to aggregate in the neurons at different parts of the brain of HD mice ( Alpaugh et al, 2022 ). These aggregations have been linked to neuronal dysfunction and premature death.…”

Section: Resultsmentioning

confidence: 99%

The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells

Ramadan,

Mohammed,

Elnour

et al. 2023

Saudi Pharmaceutical Journal

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Section: Resultsmentioning

confidence: 99%

The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells

Ramadan,

Mohammed,

Elnour

et al. 2023

Saudi Pharmaceutical Journal

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“…Several studies have indicated that mHTT has prion-like properties that may contribute to its cell-to-cell transmission ( 57 ). Previous work showed that TNTs may serve as a route for the transport of prion-like protein between cultured cells ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain

et al. 2022

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Rhes ( RASD2 ) is a thyroid hormone–induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Rhes moves and transports the HD protein, polyglutamine-expanded huntingtin (mHTT), via tunneling nanotube (TNT)–like membranous protrusions between cultured neurons. However, similar intercellular Rhes transportation in the intact brain was unknown. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)–MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, Rhes moves to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights into interneuronal protein transport in the brain.

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“…This experimental design was informed by our desire to control and analyze the structure of the fibrils in detail, and it also is a common strategy [10][11][12]14 . Moreover, extracellular aggregates may be relevant to HD in context of cell-to-cell prion-like propagation processes 4,70 , while mutant protein fragments (including aggregates) have also been detected in CSF 4,8,71 .…”

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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Prion-like properties of the mutant huntingtin protein in living organisms: the evidence and the relevance

Cited by 10 publications

References 103 publications

The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells

The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells

Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain

Inhibitor-based modulation of huntingtin aggregation mechanisms reduces fibril toxicity

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