Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes

Adegbuyiro, Adewale; Stonebraker, Alyssa R.; Sedighi, Faezeh; Fan, Caleb K.; Hodges, Breanna; Li, Peng; Valentine, Stephen J.; Legleiter, Justin

doi:10.1021/acs.biochem.2c00212

Cited by 7 publications

(5 citation statements)

References 77 publications

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“…The oxidation of huntingtin fibrils resulted in unique morphological features and, with and without the presence of a BTLE membrane, this promoted oligomerization over fibril elongation. In the presence of a membrane, altered huntingtin-induced morphological changes as observed by AFM [145].…”

Section: Huntingtinmentioning

confidence: 99%

Applications of scanning probe microscopy in neuroscience research

McRae,

Leonenko

2024

J. Phys. Mater.

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Scanning probe microscopy techniques allow for label-free high-resolution imaging of cells, tissues, and biomolecules in physiologically relevant conditions. These techniques include atomic force microscopy (AFM), atomic force spectroscopy, and Kelvin probe force microscopy (KPFM), which enable high resolution imaging, nanomanipulation and measurement of the mechanoelastic properties of neuronal cells, as well as scanning ion conductance microscopy (SICM), which combines electrophysiology and imaging in living cells. The combination of scanning probe techniques with optical spectroscopy, such as with AFM-IR and tip-enhanced Raman spectroscopy (TERS), allows for the measurement of topographical maps along with chemical identity, enabled by spectroscopy. In this work, we review applications of these techniques to neuroscience research, where they have been used to study the morphology and mechanoelastic properties of neuronal cells and brain tissues, and to study changes in these as a result of chemical or physical stimuli. Cellular membrane models are widely used to investigate the interaction of the neuronal cell membrane with proteins associated with various neurological disorders, where scanning probe microscopy and associated techniques provide significant improvement in the understanding of these processes on a cellular and molecular level.

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Section: Huntingtinmentioning

confidence: 99%

Applications of scanning probe microscopy in neuroscience research

McRae,

Leonenko

2024

J. Phys. Mater.

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“…Nt17 plays a primary role by facilitating lipid binding via the formation of an amphipathic α-helix [32]. The influence of lipids on htt aggregation can be modified by post-translational modifications within Nt17 [59][60][61][62]. Here, four different polyQ peptides with differing combinations of flanking sequences were used to determine if flanking sequences altered the seeding efficiency of fibrils formed in the presence of lipids.…”

Section: Plos Onementioning

confidence: 99%

The polyglutamine domain is the primary driver of seeding in huntingtin aggregation

Skeens,

Siriwardhana,

Massinople

et al. 2024

PLoS ONE

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Huntington’s Disease (HD) is a fatal, neurodegenerative disease caused by aggregation of the huntingtin protein (htt) with an expanded polyglutamine (polyQ) domain into amyloid fibrils. Htt aggregation is modified by flanking sequences surrounding the polyQ domain as well as the binding of htt to lipid membranes. Upon fibrillization, htt fibrils are able to template the aggregation of monomers into fibrils in a phenomenon known as seeding, and this process appears to play a critical role in cell-to-cell spread of HD. Here, exposure of C. elegans expressing a nonpathogenic N-terminal htt fragment (15-repeat glutamine residues) to preformed htt-exon1 fibrils induced inclusion formation and resulted in decreased viability in a dose dependent manner, demonstrating that seeding can induce toxic aggregation of nonpathogenic forms of htt. To better understand this seeding process, the impact of flanking sequences adjacent to the polyQ stretch, polyQ length, and the presence of model lipid membranes on htt seeding was investigated. Htt seeding readily occurred across polyQ lengths and was independent of flanking sequence, suggesting that the structured polyQ domain within fibrils is the key contributor to the seeding phenomenon. However, the addition of lipid vesicles modified seeding efficiency in a manner suggesting that seeding primarily occurs in bulk solution and not at the membrane interface. In addition, fibrils formed in the presence of lipid membranes displayed similar seeding efficiencies. Collectively, this suggests that the polyQ domain that forms the amyloid fibril core is the main driver of seeding in htt aggregation.

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“…Several PTMs localized in the Nt17 domain have been shown to modulate the structure, ,− aggregation, ,,,− toxicity, ,,, clearance, ,, nuclear translocation, , and membrane interaction. ,,, A decreased level of phosphorylated T3 was found in neuronally differentiated induced pluripotent stem cell lines from HD patient . Phosphorylation of mutant Httex1 at S13 and S16 mediated by TBK1 (TANK-binding kinase 1) decreases Httex1 aggregation and inclusion formation in different cellular models and a C. elegans model of HD .…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Post-translational Modifications on the Membrane Interaction of Huntingtin Protein

Zhang,

Gehin,

Abriata

et al. 2024

ACS Chem. Neurosci.

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Huntington's disease is a neurodegenerative disorder caused by an expanded polyglutamine stretch near the N-terminus of the huntingtin (HTT) protein, rendering the protein more prone to aggregate. The first 17 residues in HTT (Nt17) interact with lipid membranes and harbor multiple post-translational modifications (PTMs) that can modulate HTT conformation and aggregation. In this study, we used a combination of biophysical studies and molecular simulations to investigate the effect of PTMs on the helicity of Nt17 in the presence of various lipid membranes. We demonstrate that anionic lipids such as PI4P, PI(4,5)P2, and GM1 significantly enhance the helical structure of unmodified Nt17. This effect is attenuated by single acetylation events at K6, K9, or K15, whereas tri-acetylation at these sites abolishes Nt17− membrane interaction. Similarly, single phosphorylation at S13 and S16 decreased but did not abolish the POPG and PIP2-induced helicity, while dual phosphorylation at these sites markedly diminished Nt17 helicity, regardless of lipid composition. The helicity of Nt17 with phosphorylation at T3 is insensitive to the membrane environment. Oxidation at M8 variably affects membrane-induced helicity, highlighting a lipid-dependent modulation of the Nt17 structure. Altogether, our findings reveal differential effects of PTMs and crosstalks between PTMs on membrane interaction and conformation of HTT. Intriguingly, the effects of phosphorylation at T3 or single acetylation at K6, K9, and K15 on Nt17 conformation in the presence of certain membranes do not mirror that observed in the absence of membranes. Our studies provide novel insights into the complex relationship between Nt17 structure, PTMs, and membrane binding.

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Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes

Cited by 7 publications

References 77 publications

Applications of scanning probe microscopy in neuroscience research

Applications of scanning probe microscopy in neuroscience research

The polyglutamine domain is the primary driver of seeding in huntingtin aggregation

Differential Effects of Post-translational Modifications on the Membrane Interaction of Huntingtin Protein

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