Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease. Author Todd Greco, Christopher Secker, Eduardo Ramos, Joel Federspiel, Jeh-Ping Liu, Alma Perez, Ismael Al-Ramahi, Jeffrey Cantle, Jeffrey Carroll, Juan Botas, Scott Zeitlin, Erich Wanker, Ileana Cristea Publication Year 2022 Type Journal Article 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 Animals, Drosophila, Disease Models, Animal, Mice, Neurodegenerative Diseases, Corpus Striatum, Huntington Disease, Huntingtin Protein Journal Cell Syst Volume 13 Issue 4 Pages 304-320.e5 Date Published 2022 Apr 20 ISSN Number 2405-4720 DOI 10.1016/j.cels.2022.01.005 Alternate Journal Cell Syst PMCID PMC9317655 PMID 35148841 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML