Implications of the Orb2 Amyloid Structure in Huntington's Disease

Abstract

Huntington's disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington's disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain.

Keywords: CPEB; Cryo-EM; Huntington’s disease; Orb2; functional amyloids; huntingtin; polyglutamine.

Figure 1

General view of the Orb2 amyloid structure. Side view of the reconstructed Orb2 amyloid core showing the ~4.75 Å separation between β-strands, typical of the amyloid fold (A), and cross-sectional view of one molecular layer of the calculated atomic model (B) [42]. Glutamines are colored in dark blue, while histidines are colored in light blue. In some histidine residues, a major and minor occupancy, alternative sidechain conformations are shown (arrow heads). Leucine and serine residues are represented in gray.

Figure 2

Molecular architecture of Orb2 and Huntingtin amyloids. (A) Schematic of the antiparallel hairpin-like fold adopted by head-extracted Orb2 filaments, derived from the cryo-EM structure. Three Orb2 molecules per molecular layer form continuous in-register parallel β-sheets. Different tone of blue represents the different amino acid composition for each β-strand of the hairpin. Amyloid forming sequence is indicated in the top. (B) Schematic of the antiparallel β-hairpin adopted by in vitro-assembled HTTex1 amyloid, derived from ssNMR data. One single HTTex1 molecule contributes to two molecular layers to form antiparallel β-sheets. Different tone of green represents the two differently structured β-strand types of the β-hairpin. (C) Model of a multilayer packing of the parallel polyQ β-sheets, obtained by extending the Orb2 inter-digitated cross-β structure on both sides. Blue dashed line represents the hairpin turn. The extended glutamine side chains form a steric zipper interface to allow an ~8 Å distance between β-sheets. (D) Proposed in vivo HTTex1 filament model based on the multilayer polyQ packing showed in (C). Stacks of hairpins or meanders of similar β-strand lengths (highlighted in red), are viewed across the filament axis.