Expanded polyglutamine embedded in the endoplasmic reticulum causes membrane distortion and coincides with Bax insertion

Ueda, Masashi; Li, Shimo; Itoh, Masanori; Wang, Miao-xing; Hayakawa, Miki; Islam, Saiful; Tana,; Nakagawa, K.; Chen, Huayue; Nakagawa, Toshiyuki

doi:10.1016/j.bbrc.2016.04.034

Cited by 15 publications

(31 citation statements)

References 15 publications

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“…Computational studies suggested that the reduced affinity of Nt 17 for lipid membranes caused by acetylation may be due to a number of factors associated with removal of the positive charge, including altered hydrogen bonding (both intrapeptide and peptide-phospholipid) and electrostatic interactions. As aberrant htt-lipid interactions have been implicated in a variety of toxic mechanisms (50,51), understanding how acetylation of Nt 17 impacts htt aggregation and its interaction with membranous surfaces could lead to therapeutic interventions for HD. For example, acetylation in Nt 17 is reduced in htt, which contains expanded polyQ domains in comparison with the wild-type (44), and our data indicate that acetylation reduces the affinity of htt for lipid membranes and has a protective effect against htt toxicity in cell cultures.…”

Section: Discussionmentioning

confidence: 99%

“…Amino-terminal mutant htt fragments aggregate on and damage a variety of phospholipid bilayers, suggesting that phospholipid interactions may play a role in htt-related toxicity (19,23,49). Perinuclear inclusions of htt disrupt the nuclear envelope in a mouse model of HD (50), and expanded polyQ embedded in the ER is associated with membrane distortion (51). As a result, determining the factors that regulate the affinity of htt for membranes is critical not only for understanding the normal functions of htt but also for identifying ways to modify htt-lipid interactions for potential therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

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Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding

Chaibva

Jawahery

Pilkington

et al. 2016

Biophysical Journal

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Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an expanded polyglutamine (polyQ) domain near the N-terminus of the huntingtin (htt) protein. Expanded polyQ leads to htt aggregation. The first 17 amino acids (Nt(17)) in htt comprise a lipid-binding domain that undergoes a number of posttranslational modifications that can modulate htt toxicity and subcellular localization. As there are three lysines within Nt(17), we evaluated the impact of lysine acetylation on htt aggregation in solution and on model lipid bilayers. Acetylation of htt-exon1(51Q) and synthetic truncated htt-exon 1 mimicking peptides (Nt(17)-Q35-P10-KK) was achieved using a selective covalent label, sulfo-N-hydroxysuccinimide (NHSA). With this treatment, all three lysine residues (K6, K9, and K15) in Nt(17) were significantly acetylated. N-terminal htt acetylation retarded fibril formation in solution and promoted the formation of larger globular aggregates. Acetylated htt also bound lipid membranes and disrupted the lipid bilayer morphology less aggressively compared with the wild-type. Computational studies provided mechanistic insights into how acetylation alters the interaction of Nt(17) with lipid membranes. Our results highlight that N-terminal acetylation influences the aggregation of htt and its interaction with lipid bilayers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding

Chaibva

Jawahery

Pilkington

et al. 2016

Biophysical Journal

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“…266, 267 Membrane degradation of the nuclear envelope, ER, and mitochondria has been described to the presence of mutant htt, 76, 162 and expanded polyQ can generically distort ER membranes and the nuclear envelope in cell culture. 163 Stabilized oligomers species of htt are associated with mitochondrial structural proteins, and can lead to mitochondrial fragmentation, abnormal mitochondrial dynamics, and oxidative DNA damage. 268 …”

Section: Interaction With Lipids Influence Polyq Aggregation and Locamentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

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“… 41 − 46 Perinuclear inclusions of htt have been linked to disruption of the nuclear envelope in HD mouse models, 36 and expanded polyQ can embed into ER, resulting in membrane distortion. 47 …”

Section: Introductionmentioning

confidence: 99%

Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes

et al. 2018

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Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt and lipid membranes. SM composition is altered in HD, and GM1 has been shown to have protective effects in animal models of HD. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy (AFM) were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added SM or GM1. The addition of either SM or GM1 decreased htt insertion into the lipid monolayers. However, TBLE vesicles with an increased SM content were more susceptible to htt-induced permeabilization, whereas GM1 had no effect on permeablization. Pure TBLE bilayers and TBLE bilayers enriched with GM1 developed regions of roughened, granular morphologies upon exposure to htt-exon1, but plateau-like domains with a smoother appearance formed in bilayers enriched with SM. Oligomeric aggregates were observed on all bilayer systems regardless of induced morphology. Collectively, these observations suggest that the lipid composition and its subsequent effects on membrane material properties strongly influence htt binding and aggregation on lipid membranes.

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Expanded polyglutamine embedded in the endoplasmic reticulum causes membrane distortion and coincides with Bax insertion

Cited by 15 publications

References 15 publications

Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding

Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes

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