Title | Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Greco, TM, Secker, C, Ramos, ESilva, Federspiel, JD, Liu, J-P, Perez, AM, Al-Ramahi, I, Cantle, JP, Carroll, JB, Botas, J, Zeitlin, SO, Wanker, EE, Cristea, IM |
Journal | Cell Syst |
Volume | 13 |
Issue | 4 |
Pagination | 304-320.e5 |
Date Published | 2022 Apr 20 |
ISSN | 2405-4720 |
Keywords | Animals, Corpus Striatum, Disease Models, Animal, Drosophila, Huntingtin Protein, Huntington Disease, Mice, Neurodegenerative Diseases |
Abstract | <p>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.</p> |
DOI | 10.1016/j.cels.2022.01.005 |
Alternate Journal | Cell Syst |
PubMed ID | 35148841 |