Dynamics of Huntingtin Protein Interactions in the Striatum Identifies Candidate Modifiers of Huntington Disease

Authors

Todd M Greco
Christopher Secker
Eduardo Silva Ramos
Joel D Federspiel
Jeh-Ping Liu
Alma M Perez
Ismael Al-Ramahi
Jeffrey P Cantle
Jeffrey B Carroll
Juan Botas
Scott O Zeitlin
Erich E Wanker
Ileana M Cristea

Language

English

Publication Date

4-20-2022

Journal

Cell Systems

DOI

10.1016/j.cels.2022.01.005

PMID

35148841

PMCID

PMC9317655

PubMedCentral® Posted Date

4-20-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

Huntington’s 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, Corpus Striatum, Disease Models, Animal, Drosophila, Huntingtin Protein, Huntington Disease, Mice, Neurodegenerative Diseases, immunoaffinity purification mass spectrometry, protein interactions, label-free quantification, metabolic labeling, vesicle trafficking, SNARE, Arp2/3, AMPA receptors, LuTHy, D. melanogaster, synaptic biology

Published Open-Access

yes

Recommended Citation

Greco, Todd M; Secker, Christopher; Ramos, Eduardo Silva; et al., "Dynamics of Huntingtin Protein Interactions in the Striatum Identifies Candidate Modifiers of Huntington Disease" (2022). Duncan NRI Faculty and Staff Publications. 67.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/67