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Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation

Huntington's disease (HD) is a neurodegenerative disease resulting from an expansion of the polyglutamine (polyQ) domain within the huntingtin protein (htt). PolyQ expansion triggers toxic aggregation and alters htt/lipid interactions. The first 17 amino acids at the N‐terminus of htt (Nt17) ha...

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Autores principales: Stonebraker, Alyssa R., Beasley, Maryssa, Massinople, Sophia, Wunder, Michelle, Li, Peng, Valentine, Stephen J., Legleiter, Justin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127259/
https://www.ncbi.nlm.nih.gov/pubmed/37052951
http://dx.doi.org/10.1002/pro.4642
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author Stonebraker, Alyssa R.
Beasley, Maryssa
Massinople, Sophia
Wunder, Michelle
Li, Peng
Valentine, Stephen J.
Legleiter, Justin
author_facet Stonebraker, Alyssa R.
Beasley, Maryssa
Massinople, Sophia
Wunder, Michelle
Li, Peng
Valentine, Stephen J.
Legleiter, Justin
author_sort Stonebraker, Alyssa R.
collection PubMed
description Huntington's disease (HD) is a neurodegenerative disease resulting from an expansion of the polyglutamine (polyQ) domain within the huntingtin protein (htt). PolyQ expansion triggers toxic aggregation and alters htt/lipid interactions. The first 17 amino acids at the N‐terminus of htt (Nt17) have a propensity to form an amphipathic α‐helix crucial to aggregation and membrane binding. Htt interacts closely with a variety of membrane systems including those of the endoplasmic reticulum, mitochondria, nuclear envelope, and plasma membrane. Membrane composition heavily influences both htt aggregation and lipid interactions, and cholesterol is a crucial membrane component that modulates properties such as fluidity, permeability, and organization. In HD, cholesterol homeostasis is disrupted, and likely plays a role in toxicity. The objective of these studies was to identify the impact of cholesterol on htt aggregation and lipid interactions in various lipid systems. Lipid systems of POPC, DOPC, and POPG with varied levels of exogenously added cholesterol were exposed to htt, and the influences on aggregation, lipid binding, and htt/lipid complexation were evaluated using thioflavin‐T aggregation assays, atomic force microscopy, colorimetric lipid binding assays, and mass spectrometry. The addition of cholesterol to DOPC vesicles enhanced htt aggregation. In the presence of vesicles of either POPC or POPG, the addition of cholesterol reduced htt aggregation. Htt/lipid binding decreased for POPC and increased for both DOPC and POPG with increasing cholesterol content, with observed differences in htt/lipid complexation. Altered cholesterol content influences htt aggregation, lipid binding, and complexation differently depending on overall lipid composition.
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spelling pubmed-101272592023-05-01 Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation Stonebraker, Alyssa R. Beasley, Maryssa Massinople, Sophia Wunder, Michelle Li, Peng Valentine, Stephen J. Legleiter, Justin Protein Sci Full‐length Papers Huntington's disease (HD) is a neurodegenerative disease resulting from an expansion of the polyglutamine (polyQ) domain within the huntingtin protein (htt). PolyQ expansion triggers toxic aggregation and alters htt/lipid interactions. The first 17 amino acids at the N‐terminus of htt (Nt17) have a propensity to form an amphipathic α‐helix crucial to aggregation and membrane binding. Htt interacts closely with a variety of membrane systems including those of the endoplasmic reticulum, mitochondria, nuclear envelope, and plasma membrane. Membrane composition heavily influences both htt aggregation and lipid interactions, and cholesterol is a crucial membrane component that modulates properties such as fluidity, permeability, and organization. In HD, cholesterol homeostasis is disrupted, and likely plays a role in toxicity. The objective of these studies was to identify the impact of cholesterol on htt aggregation and lipid interactions in various lipid systems. Lipid systems of POPC, DOPC, and POPG with varied levels of exogenously added cholesterol were exposed to htt, and the influences on aggregation, lipid binding, and htt/lipid complexation were evaluated using thioflavin‐T aggregation assays, atomic force microscopy, colorimetric lipid binding assays, and mass spectrometry. The addition of cholesterol to DOPC vesicles enhanced htt aggregation. In the presence of vesicles of either POPC or POPG, the addition of cholesterol reduced htt aggregation. Htt/lipid binding decreased for POPC and increased for both DOPC and POPG with increasing cholesterol content, with observed differences in htt/lipid complexation. Altered cholesterol content influences htt aggregation, lipid binding, and complexation differently depending on overall lipid composition. John Wiley & Sons, Inc. 2023-05-01 /pmc/articles/PMC10127259/ /pubmed/37052951 http://dx.doi.org/10.1002/pro.4642 Text en © 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full‐length Papers
Stonebraker, Alyssa R.
Beasley, Maryssa
Massinople, Sophia
Wunder, Michelle
Li, Peng
Valentine, Stephen J.
Legleiter, Justin
Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title_full Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title_fullStr Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title_full_unstemmed Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title_short Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
title_sort cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation
topic Full‐length Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127259/
https://www.ncbi.nlm.nih.gov/pubmed/37052951
http://dx.doi.org/10.1002/pro.4642
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