@article{49606c0aba5944aba88df82ed23d7044,
title = "Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease",
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 = "AMPA receptors, Arp2/3, D. melanogaster, LuTHy, SNARE, immunoaffinity purification-mass spectrometry, label-free quantification, metabolic labeling, protein interactions, synaptic biology, vesicular trafficking",
author = "Greco, {Todd M.} and Christopher Secker and Ramos, {Eduardo Silva} and Federspiel, {Joel D.} and Liu, {Jeh Ping} and Perez, {Alma M.} and Ismael Al-Ramahi and Cantle, {Jeffrey P.} and Carroll, {Jeffrey B.} and Juan Botas and Zeitlin, {Scott O.} and Wanker, {Erich E.} and Cristea, {Ileana M.}",
note = "Funding Information: We would like to thank Thomas Vogt, Daniel Lavery, Ravi Iyer, Brinda Prasad, and the investigators of the CHDI PPI working group for thoughtful discussions about experimental design and data interpretation. I.M.C. and E.E.W. are grateful for funding from the CHDI Foundation, USA. E.E.W. is supported by the Helmholtz Association (iMed and Helmholtz-Israel Initiative on Personalized Medicine, Germany). S.O.Z. and J.-P.L. are supported by NIH NS077926 and NS090914. J.B. is supported by AG/NIA/NIH R01 AG057339. T.M.G. and I.M.C. conceived and led the study, wrote the manuscript, and all authors contributed to the manuscript. J.-P.L. and S.O.Z. bred the HD mouse models and dissected brain tissues. T.M.G. J.D.F. and I.M.C. conceived and designed the IP-MS experiments. T.M.G. performed and analyzed the IP-MS experiments. C.S. E.S.R. and E.E.W. designed and E.S.R. and C.S. performed the LuTHy experiments and the data analysis. J.B. J.P.C. and J.B.C. conceived, A.M.P. performed, and I.A.-R. performed, designed, and analyzed the Drosophila motor performance assays. The authors declare no competing interests. Funding Information: We would like to thank Thomas Vogt, Daniel Lavery, Ravi Iyer, Brinda Prasad, and the investigators of the CHDI PPI working group for thoughtful discussions about experimental design and data interpretation. I.M.C. and E.E.W. are grateful for funding from the CHDI Foundation, USA. E.E.W. is supported by the Helmholtz Association (iMed and Helmholtz-Israel Initiative on Personalized Medicine, Germany). S.O.Z. and J.-P.L. are supported by NIH NS077926 and NS090914 . J.B. is supported by AG / NIA / NIH R01 AG057339 . Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = apr,
day = "20",
doi = "10.1016/j.cels.2022.01.005",
language = "English (US)",
volume = "13",
pages = "304--320.e5",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "4",
}