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

TitleDynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsGreco, 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
JournalCell Syst
Date Published2022 Apr 20
KeywordsAnimals, Corpus Striatum, Disease Models, Animal, Drosophila, Huntingtin Protein, Huntington Disease, Mice, Neurodegenerative Diseases

<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>

Alternate JournalCell Syst
PubMed ID35148841
PubMed Central IDPMC9317655
Grant ListR01 AG057339 / AG / NIA NIH HHS / United States
R01 NS077926 / NS / NINDS NIH HHS / United States
R01 NS090914 / NS / NINDS NIH HHS / United States