The Nt17 Domain and its Helical Conformation Regulate the Aggregation, Cellular Properties and Neurotoxicity of Mutant Huntingtin Exon 1. Issue 21 (15th October 2021)

• Record Type: Journal Article
• Authors: Vieweg, Sophie; Mahul-Mellier, Anne-Laure; Ruggeri, Francesco S.; Riguet, Nathan; DeGuire, Sean M.; Chiki, Anass; Cendrowska, Urszula; Dietler, Giovanni; Lashuel, Hilal A.
• Is Part Of: Journal of molecular biology. Volume 433:Issue 21(2021)
• Publication Date: 2021-10-15
• Subjects: Huntington's disease -- Httex1 -- Nt17 -- aggregation -- neuronal uptake; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167222
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: The Nt17 and polyQ domains synergistically promote Httex1 aggregation. The Nt17 domain is a key determinant of the lateral association and morphology of fibrils. The Nt17 domain and conformation regulate the nuclear/cytoplasmic distribution and toxicity of Httex1. Nt17 conformation is a key determinant of Httex1 fibril membrane interaction and cellular uptake. Nt17 serves as one of the master regulators of Httex1 aggregation, cellular uptake and toxicity. Abstract: Converging evidence points to the N-terminal domain comprising the first 17 amino acids of the Huntingtin protein (Nt17) as a key regulator of its aggregation, cellular properties and toxicity. In this study, we further investigated the interplay between Nt17 and the polyQ domain repeat length in regulating the aggregation and inclusion formation of exon 1 of the Huntingtin protein (Httex1). In addition, we investigated the effect of removing Nt17 or modulating its local structure on the membrane interactions, neuronal uptake, and toxicity of monomeric or fibrillar Httex1. Our results show that the polyQ and Nt17 domains synergistically modulate the aggregation propensity of Httex1 and that the Nt17 domain plays important roles in shaping the surface properties of mutant Httex1 fibrils and regulating their poly-Q-dependent growth, lateral association and neuronal uptake. Removal of Nt17 or disruption of its transient helical conformations slowed the aggregation of monomeric Httex1 in vitro, reduced inclusion formation in cells, enhanced the neuronal uptake and nuclear accumulation of monomeric Httex1 proteins, and was sufficient to prevent cell death induced by Httex1 72Q overexpression. Finally, we demonstrate that the uptake of Httex1 fibrils into primary neurons and the resulting toxicity are strongly influenced by mutations and phosphorylation events that influence the local helical propensity of Nt17. Altogether, our results demonstrate that the Nt17 domain serves as one of the key master regulators of Htt aggregation, internalization, and toxicity and represents an attractive target for inhibiting Htt aggregate formation, inclusion formation, and neuronal toxicity.