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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)304-320.e5
JournalCell Systems
Volume13
Issue number4
DOIs
StatePublished - Apr 20 2022

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Keywords

  • AMPA receptors
  • Arp2/3
  • D. melanogaster
  • LuTHy
  • SNARE
  • immunoaffinity purification-mass spectrometry
  • label-free quantification
  • metabolic labeling
  • protein interactions
  • synaptic biology
  • vesicular trafficking

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