@article{ea1b9531a613428b964aadfbc7815897,
title = "Mutant Huntingtin Disrupts the Nuclear Pore Complex",
abstract = "Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.",
keywords = "C9ORF72, Huntington's disease, KPT-350, O-GlcNAc, RAN translation, Thiamet-G, induced pluripotent stem cell, neurodegeneration, nuclear pore complex, nucleocytoplasmic transport",
author = "Grima, {Jonathan C.} and Daigle, {J. Gavin} and Nicolas Arbez and Cunningham, {Kathleen C.} and Ke Zhang and Joseph Ochaba and Charlene Geater and Eva Morozko and Jennifer Stocksdale and Glatzer, {Jenna C.} and Pham, {Jacqueline T.} and Ishrat Ahmed and Qi Peng and Harsh Wadhwa and Olga Pletnikova and Troncoso, {Juan C.} and Wenzhen Duan and Snyder, {Solomon H.} and Ranum, {Laura P.W.} and Thompson, {Leslie M.} and Lloyd, {Thomas E.} and Ross, {Christopher A.} and Rothstein, {Jeffrey D.}",
note = "Funding Information: Funded by grants from the NIH (R01NS094239 and R01NS085207 to J.D.R., C.A.R., L.M.T., L.P.W.R., S.H.S., and T.E.L.), National Science Foundation Graduate Research Fellowship Award (J.C. Grima), Thomas Shortman Training Fund Graduate Award (J.C. Grima), Axol Science Award (J.C. Grima), NIH Training in Neurotherapeutics Discovery and Development for Academic Scientists (J.C. Grima), MDI Biological Laboratory QFM Chroma Fellowship Award (J.C. Grima), National Science Foundation (J.O.), CIRM Training Grant (C.G.) and the Johns Hopkins Brain Science Institute (J.D.R.). Drs. Ross, Troncoso, and Pletnikova provided human tissue and demographics. We wish to thank Michael J. Matunis for helpful discussions, Svetlana Videnskey for construct preparations and technical support, Natasha Zachara and the CardioPEG Core at Johns Hopkins (NHLBI PO1 HL107153) for providing Thiamet-G, Uzma Hussain for technical assistance, and Sharon Tamir/Karyopharm Therapeutics for supplying KPT-350. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = apr,
day = "5",
doi = "10.1016/j.neuron.2017.03.023",
language = "English (US)",
volume = "94",
pages = "93--107.e6",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}