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Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease

Item Type:Article
Title:Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease
Creators Name:Greco, T.M. and Secker, C. and Silva Ramos, E. and Federspiel, J.D. and Liu, J.P. and Perez, A.M. and Al-Ramahi, I. and Cantle, J.P. and Carroll, J.B. and Botas, J. and Zeitlin, S.O. and Wanker, E.E. and Cristea, I.M.
Abstract:Huntington disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid and behavioral assays in HD human cell and Drosophila models, respectively. Validated, disease-relevant mHTT-dependent interactions encompass mediators of synaptic neurotransmission (SNAREs and glutamate receptors) and lysosomal acidification (V-ATPase). Our study provides a resource for understanding mHTT-dependent dysfunction in cortico-striatal cellular networks, partly through impaired synaptic communication and endosomal-lysosomal system. A record of this paper's Transparent Peer Review process is included in the supplemental information.
Keywords:Immunoaffinity Purification-Mass Spectrometry, Protein Interactions, Label-Free Quantification, Metabolic Labeling, Vesicular Trafficking, SNARE, Arp2/3, AMPA receptors, LuTHy, Synaptic Biology, Animals, D. melanogaster, Drosophila melanogaster, Mice
Source:Cell Systems
Publisher:Cell Press / Elsevier
Page Range:304-320.e5
Date:22 April 2022
Additional Information:Copyright © 2022 Elsevier Inc. All rights reserved.
Official Publication:https://doi.org/10.1016/j.cels.2022.01.005
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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