@article{f1f32e93c7db43a580d78868ebcbf51e,
title = "Identifying polyglutamine protein species in situ that best predict neurodegeneration",
abstract = "Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.",
author = "Jason Miller and Montserrat Arrasate and Elizabeth Brooks and Libeu, {Clare Peters} and Justin Legleiter and Danny Hatters and Jessica Curtis and Kenneth Cheung and Preethi Krishnan and Siddhartha Mitra and Kartika Widjaja and Shaby, {Benjamin A.} and Lotz, {Gregor P.} and Yvonne Newhouse and Mitchell, {Emily J.} and Alex Osmand and Michelle Gray and Vanitha Thulasiramin and Fr{\"a}ric Saudou and Mark Segal and Yang, {X. William} and Eliezer Masliah and Thompson, {Leslie M.} and Muchowski, {Paul J.} and Weisgraber, {Karl H.} and Steven Finkbeiner",
note = "Funding Information: We thank A. Kazantzev, D. Housman and the Hereditary Disease Foundation (HDF) for pcDNA3.1-Httex1-(Q46, Q97)-GFP plasmids. We also thank R. Truant for eGFP-full-length Htt-β-galactosidase (Q17, Q138) plasmids, M. Diamond for the HA-AR (Q25, Q65) plasmids, J. Burke and CHDI, Inc. for the GST-atrophin-1 (Q19, Q81) plasmids, R. Kopito for Httex1-CFP (Q25, Q97) and Httex1-YFP (Q25, Q97) plasmids, D. Devys for GST-Htt-171 (Q66, Q142) plasmids, R. Pittman for Myc-ataxin-3 (Q27 Q78) plasmids, O. Onodera for Httex1-mCFP (Q17, Q58) and Httex1-mYFP (Q17, Q58) plasmids, P. Bjorkman for the thio-Httex1-Q39-His6 plasmid and P. Daugherty for mammalian codon-optimized CyPet and YPet plasmids. We thank P. Patterson for the monoclonal antibodies MW1, MW7 and MW8 and C. Glabe for the oligomer-specific polyclonal antibody. We thank members of the Finkbeiner lab for useful discussions, S. Ordway and G. Howard for editorial assistance, K. Nelson for administrative assistance and M. Sutherland for her interest and support. Primary support for this work was provided by the Lieberman Award of the HDF and the US National Institute of Neurological Disease and Stroke (S.F.). Additional support was provided by the National Institute of Aging, the High Q Foundation, the Huntington{\textquoteright}s Disease Society of America, the National Center for Research Resources, the Taube-Koret Center for Huntington{\textquoteright}s Disease Research, the Hellman Family Foundation Program for Alzheimer{\textquoteright}s Disease Research and the J. David Gladstone Institutes (S.F.). M.A. and J.M. are supported by the Hillblom Foundation. J.M. and S.M. are supported by the US National Institutes of Health (NIH)–National Institute of General Medical Sciences University of California San Fransisco Medical Scientist Training Program. J.M is supported by a fellowship from the Achievement Rewards for College Scientists Foundation. D.H. is supported by a postdoctoral fellowship from the John Douglas French Alzheimer{\textquoteright}s Foundation. J.L. and A.O. are supported by the HDF. E.J.M. is supported by a grant from the NIH. The animal care facility was partly supported by an NIH Extramural Research Facilities Improvement Project. The electron microscopy core (E.M.) is supported by a grant from the National Institute of Neurological Disease and Stroke.",
year = "2011",
month = dec,
doi = "10.1038/nchembio.694",
language = "English (US)",
volume = "7",
pages = "925--934",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Research",
number = "12",
}