Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington’s disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein compositi...

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Bibliographic Details
Published in:Nature communications Vol. 12; no. 1; pp. 6579 - 27
Main Authors: Riguet, Nathan, Mahul-Mellier, Anne-Laure, Maharjan, Niran, Burtscher, Johannes, Croisier, Marie, Knott, Graham, Hastings, Janna, Patin, Alice, Reiterer, Veronika, Farhan, Hesso, Nasarov, Sergey, Lashuel, Hilal A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 12.11.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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14/28
14/35
631/378/1689/1558
631/80/470/2284
82/29
82/58
96/109
Agglomeration
Animals
Biochemical composition
Biochemistry
Cell Nucleus - metabolism
Composition
Cytoplasm - metabolism
Cytoskeleton
HEK293 Cells
Humanities and Social Sciences
Humans
Huntingtin
Huntingtin Protein - chemistry
Huntingtin Protein - genetics
Huntingtin Protein - metabolism
Huntingtin Protein - ultrastructure
Huntington Disease - metabolism
Huntington's disease
Huntingtons disease
Inclusion bodies
Inclusions
Intranuclear Inclusion Bodies - metabolism
Lipids
Mammalian cells
Mice
Mice, Inbred C57BL
multidisciplinary
Neurodegeneration
Neurons - metabolism
Organelles
Pathogenesis
Peptides - chemistry
Polyglutamine
Protein Aggregation, Pathological
Protein composition
Proteins
Proteome
Quality control
Science
Science (multidisciplinary)
Toxicity
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington’s disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt cytoplasmic and nuclear inclusions in mammalian cells and primary neurons overexpressing mutant exon1 of the Htt protein. Our findings provide unique insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve the polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; the recruitment and accumulation of remodeled or dysfunctional membranous organelles, and the impairment of the protein quality control and degradation machinery. We also show that nuclear and cytoplasmic Htt inclusions exhibit distinct biochemical compositions and ultrastructural properties, suggesting different mechanisms of aggregation and toxicity. The mechanisms underlying Huntingtin protein (Htt) aggregation are not fully understood. Here the authors perform a detailed investigation of the ultrastructural and biochemical properties of huntingtin cytoplasmic and nuclear inclusions, and reveal that they form via distinct mechanisms and exert their toxicity via different pathways.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-26684-z