Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease

Neurobiology of Disease
Kenneth W DromboskyRonald Wetzel

Abstract

In Huntington disease (HD), an expanded polyglutamine (polyQ > 37) sequence within huntingtin (htt) exon1 leads to enhanced disease risk. It has proved difficult, however, to determine whether the toxic form generated by polyQ expansion is a misfolded or avid-binding monomer, an α-helix-rich oligomer, or a β-sheet-rich amyloid fibril. Here we describe an engineered htt exon1 analog featuring a short polyQ sequence that nonetheless quickly forms amyloid fibrils and causes HD-like toxicity in rat neurons and Drosophila. Additional modifications within the polyQ segment produce htt exon1 analogs that populate only spherical oligomers and are non-toxic in cells and flies. Furthermore, in mixture with expanded-polyQ htt exon1, the latter analogs in vitro suppress amyloid formation and promote oligomer formation, and in vivo rescue neurons and flies expressing mhtt exon1 from dysfunction and death. Thus, in our experiments, while htt exon1 toxicity tracks with aggregation propensity, it does so in spite of the toxic construct's possessing polyQ tracts well below those normally considered to be disease-associated. That is, aggregation propensity proves to be a more accurate surrogate for toxicity than is polyQ repeat length itself, st...Continue Reading

Citations

Jun 6, 2019·Chembiochem : a European Journal of Chemical Biology·Devi WahyuningtyasJoseph Jen-Tse Huang
Aug 17, 2019·Journal of Neurochemistry·Erich E WankerSigrid Schnoegl
Oct 24, 2019·Proceedings of the National Academy of Sciences of the United States of America·Michael A MetrickByron Caughey
Apr 8, 2020·Chemistry : a European Journal·Paula OrtegaSara de Pablo
Sep 16, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mary XylakiEvangelia Emmanouilidou
Sep 25, 2020·International Journal of Molecular Sciences·Rubén HervásKausik Si
Apr 11, 2019·Frontiers in Molecular Biosciences·Sigal Rencus-LazarDana Laor
Jun 6, 2021·Biochimica Et Biophysica Acta. Biomembranes·Adewale AdegbuyiroJustin Legleiter
Jul 12, 2021·Colloids and Surfaces. B, Biointerfaces·Sharon E GrooverJustin Legleiter
Dec 28, 2019·ACS Chemical Neuroscience·Faezeh SedighiJustin Legleiter
May 11, 2019·ACS Chemical Biology·Mirella Vivoli VegaFabrizio Chiti
Nov 2, 2021·Frontiers in Molecular Neuroscience·Maria Lucia PigazziniJanine Kirstein
Dec 8, 2021·Scientific Reports·Yutaro IizukaKazuhiro Nakamura
Dec 17, 2021·ACS Applied Materials & Interfaces·Devi WahyuningtyasJoseph Jen-Tse Huang
Nov 2, 2020·Biochimica Et Biophysica Acta. Biomembranes·Maryssa BeasleyJustin Legleiter

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